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Lange G, Gnazzo F, Beeler JA. Accumbal Dopamine and Acetylcholine Dynamics during Psychostimulant Sensitization. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.03.29.646091. [PMID: 40236122 PMCID: PMC11996294 DOI: 10.1101/2025.03.29.646091] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 04/17/2025]
Abstract
Behavioral sensitization to repeated psychostimulant exposure is believed to contribute to the development of addiction. Nucleus accumbens (NAcc) dopamine (DA) is known to be a key substrate in sensitization, though recent work suggests that striatal acetylcholine (ACh) may also play a critical role. However, underlying ACh changes and their relationship to DA signaling have not been characterized. Here, we used dual-color fiber photometry to simultaneously measure DA and ACh in the NAcc shell of mice across repeated injections of cocaine or amphetamine. Repeated exposure progressively elevated locomotor activity and increased slow extracellular DA while attenuating transient DA release. Psychostimulants reduced phasic ACh transient amplitude and frequency, an effect that sensitized with repeated injections. However, the temporal coupling of DA and ACh remained unchanged. To determine whether D2 receptors (D2Rs) on cholinergic interneurons (CINs) drive this effect, we generated CIN-selective D2R knockout (KO) mice. Surprisingly, KOs continued to show an acute decrease in ACh and intact DA-ACh correlations after psychostimulant administration. However, they failed to exhibit sensitization of either DA or ACh in response to repeated psychostimulant administration. Despite this lack of sensitization in underlying neuromodulator signaling, the KO mice nevertheless exhibited behavioral sensitization, though at a slower rate than wild-type. These findings suggest that neural sensitization to psychostimulants is dependent on D2R expressed on CINs, but that behavioral sensitization is not dependent on sensitization of these underlying signals.
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Berezovskaia A, Lindsley C, Fink-Jensen A, Wörtwein G. M 4 Positive Allosteric Modulator VU0467154 Impacts Amphetamine Sensitization and Spontaneous Locomotion in Male Mice. ACS Chem Neurosci 2025; 16:868-879. [PMID: 39982140 DOI: 10.1021/acschemneuro.4c00795] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/22/2025] Open
Abstract
This study investigates the effects of the muscarinic acetylcholine receptor subtype 4 (M4) positive allosteric modulator (PAM) VU0467154 on the development, incubation, and expression of amphetamine sensitization in mice, the expression of immediate early genes in the medial prefrontal cortex after induction and expression of sensitization, as well as on spontaneous locomotion and several aspects of sensorimotor function. Mice were pretreated with VU0467154 during the induction phase, before the challenge test, or both. A separate cohort was treated during the incubation period. Tests of spontaneous locomotion and sensorimotor function were conducted after VU0467154 administration to evaluate potential side effects. Treatment with VU0467154 inhibited the development and expression of amphetamine sensitization. This was paralleled by effects on immediate early gene expression in the medial prefrontal cortex. Additionally, previous pretreatment with VU0467154 during the induction phase attenuated the expression of sensitization after a two-week incubation period. However, treatment with VU0467154 during the incubation period did not affect the expression of a sensitized response. VU0467154 significantly reduced spontaneous locomotion without impairing other aspects of sensorimotor function, as assessed by the mesh, adhesive removal, horizontal bar, and negative geotaxis tests. Global M4 knockout mice confirmed that the inhibitory effect on spontaneous locomotion was specific to M4 receptors. Our findings provide new insights into the therapeutic potential of M4 PAMs in modulating the neuroadaptations associated with psychostimulant abuse. Collectively, these results suggest that activation of M4 receptors could be a promising strategy for modulating dopaminergic signaling and reducing some behaviors associated with substance use disorder.
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Affiliation(s)
- Anna Berezovskaia
- Laboratory of Neuropsychiatry, Mental Health Centre Copenhagen, Mental Health Services in the Capital Region of Denmark and University of Copenhagen, Frederiksberg 2000, Denmark
- Copenhagen Center for Translational Research, Copenhagen University Hospital─Bispebjerg and Frederiksberg Hospital, Copenhagen 2400, Denmark
| | - Craig Lindsley
- Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, Tennessee 37232, United States
| | - Anders Fink-Jensen
- Laboratory of Neuropsychiatry, Mental Health Centre Copenhagen, Mental Health Services in the Capital Region of Denmark and University of Copenhagen, Frederiksberg 2000, Denmark
- Copenhagen Center for Translational Research, Copenhagen University Hospital─Bispebjerg and Frederiksberg Hospital, Copenhagen 2400, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen 2200, Denmark
| | - Gitta Wörtwein
- Laboratory of Neuropsychiatry, Mental Health Centre Copenhagen, Mental Health Services in the Capital Region of Denmark and University of Copenhagen, Frederiksberg 2000, Denmark
- Copenhagen Center for Translational Research, Copenhagen University Hospital─Bispebjerg and Frederiksberg Hospital, Copenhagen 2400, Denmark
- Department of Public Health, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen 1353, Denmark
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Xie Q, Dasari R, Namba MD, Buck LA, Side CM, Park K, Jackson JG, Barker JM. Astrocytic regulation of cocaine locomotor sensitization in EcoHIV infected mice. Neuropharmacology 2025; 265:110245. [PMID: 39631679 DOI: 10.1016/j.neuropharm.2024.110245] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2024] [Revised: 10/30/2024] [Accepted: 11/30/2024] [Indexed: 12/07/2024]
Abstract
Cocaine use disorder (CUD) is highly comorbid with HIV infection and worsens HIV outcomes. Preclinical research on the outcomes of HIV infection may yield crucial information on neurobehavioral changes resulting from chronic drug exposure in people living with HIV (PLWH). Repeated exposure to cocaine alters behavioral responses to cocaine. This includes development of cocaine locomotor sensitization - or increased locomotor responses to the same doses of cocaine - which depends on nucleus accumbens (NAc) neural plasticity. NAc astrocytes are key regulators of neural activity and plasticity, and their function can be impaired by cocaine exposure and HIV infection, thus implicating them as potential regulators of HIV-induced changes in behavioral response to cocaine. To characterize the effects of HIV infection on cocaine locomotor sensitization, we employed the EcoHIV mouse model in male and female mice to assess changes in locomotor responses after repeated cocaine (10 mg/kg) exposure and challenge. EcoHIV infection potentiated expression of cocaine sensitization. We also identified EcoHIV-induced increases in expression of the astrocytic nuclear marker Sox9 selectively in the NAc core. To investigate whether modulation of NAc astrocytes could reverse EcoHIV-induced deficits, we employed a chemogenetic approach. We found that chemogenetic activation of NAc astrocyte Gq signaling attenuated EcoHIV-enhanced cocaine sensitization. We propose that HIV infection contributes to cocaine behavioral sensitization and induces adaptations in NAc astrocytes, while promoting NAc astrocytic Gq-signaling can recover EcoHIV-induced behavioral changes. These findings identify potential cellular substrates of disordered cocaine-driven behavior in the context of HIV infection and point toward strategies to reduce cocaine-related behavior in PLWH.
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Affiliation(s)
- Qiaowei Xie
- Department of Pharmacology and Physiology, Drexel University College of Medicine, USA; Graduate Program in Pharmacology and Physiology, Drexel University College of Medicine, USA
| | - Rohan Dasari
- Department of Pharmacology and Physiology, Drexel University College of Medicine, USA
| | - Mark D Namba
- Department of Pharmacology and Physiology, Drexel University College of Medicine, USA
| | - Lauren A Buck
- Department of Pharmacology and Physiology, Drexel University College of Medicine, USA
| | - Christine M Side
- Department of Pharmacology and Physiology, Drexel University College of Medicine, USA
| | - Kyewon Park
- University of Pennsylvania Center for AIDS Research, USA
| | - Joshua G Jackson
- Department of Pharmacology and Physiology, Drexel University College of Medicine, USA
| | - Jacqueline M Barker
- Department of Pharmacology and Physiology, Drexel University College of Medicine, USA.
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Qiu L, Nho Y, Seilheimer RL, Kim MJ, Tufanoglu A, Williams N, Wexler A, David O, Millet B, Katherine SW, Pesaran B, Evins AE, Richardson M, Childress AR, Halpern CH. Localizing electrophysiologic cue-reactivity within the nucleus accumbens guides deep brain stimulation for opioid use disorder. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2024.12.30.630822. [PMID: 39803486 PMCID: PMC11722221 DOI: 10.1101/2024.12.30.630822] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/05/2025]
Abstract
Substance use disorder (SUD) is a significant public health concern, with over 30% of the affected population not responding to available treatments. Severe SUD is characterized by drug-cue reactivity that has been reported to predict treatment-failure. We leveraged this pathophysiological feature to optimize deep brain stimulation (DBS) of the nucleus accumbens region (NAc) in an adult with SUD. A personalized drug cue-reactivity task was administered while recording NAc region electrophysiology from a lead externalized for clinical purposes. We identified a drug cue-evoked signal in the ventral NAc associated with intensification of opioid-related cravings, which attenuated subsequent to stimulation delivered to the same area. DBS was then programmed to engage this focal region, which resulted in sustained suppression of drug-related cravings. This finding heralds the potential for personalized strategies to optimize DBS for SUD.
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Ku MJ, Kim CY, Park JW, Lee S, Jeong EY, Jeong JW, Kim WY, Kim JH. Wireless optogenetic stimulation on the prelimbic to the nucleus accumbens core circuit attenuates cocaine-induced behavioral sensitization. Neurobiol Dis 2024; 203:106733. [PMID: 39536953 DOI: 10.1016/j.nbd.2024.106733] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2024] [Revised: 11/03/2024] [Accepted: 11/07/2024] [Indexed: 11/16/2024] Open
Abstract
Behavioral sensitization is defined as the heightened and persistent behavioral response to repeated drug exposure as a manifestation of drug craving. Psychomotor stimulants such as cocaine can induce strong behavioral sensitization. In this study, we explored the effects of optogenetic stimulation of the prelimbic (PL) to the nucleus accumbnes (NAc) core on the expression of cocaine-induced behavioral sensitization. Using wireless optogenetics, we selectively stimulated the PL-NAc core circuit, and assessed the effects of this treatment on cocaine-induced locomotor activity and accompanying changes in neuronal activation and dendritic spine density. Our findings revealed that optogenetic stimulation of the PL-NAc core circuit effectively suppressed the cocaine-induced locomotor sensitization, accompanied by a reduction in c-Fos expression within the NAc core. Moreover, optogenetic stimulation led to reduction in dendritic spine density, particularly thin and mushroom spine densities, in the NAc core. This study demonstrates that cocaine-induced locomotor sensitization can be regulated by optogenetic stimulation of the PL-NAc core circuit, providing insights into the crucial role of this circuit in psychomotor stimulant addiction.
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Affiliation(s)
- Min Jeong Ku
- Department of Medical Sciences, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
| | - Choong Yeon Kim
- School of Electrical Engineering, Korea Advanced Institute of Science and Technology, Daejeon 34141, Republic of Korea; KAIST Information & Electronics Research Institute, Daejeon 34141, Republic of Korea
| | - Jong Woo Park
- Department of Medical Sciences, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
| | - Seohyeon Lee
- Department of Medical Sciences, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
| | - Eun Young Jeong
- School of Electrical Engineering, Korea Advanced Institute of Science and Technology, Daejeon 34141, Republic of Korea
| | - Jae-Woong Jeong
- School of Electrical Engineering, Korea Advanced Institute of Science and Technology, Daejeon 34141, Republic of Korea; KAIST Institute for NanoCentury, Daejeon 34141, Republic of Korea; KAIST Institute for Health Science and Technology, Daejeon 34141, Republic of Korea.
| | - Wha Young Kim
- Department of Physiology, Yonsei University College of Medicine, Seoul 03722, Republic of Korea.
| | - Jeong-Hoon Kim
- Department of Medical Sciences, Yonsei University College of Medicine, Seoul 03722, Republic of Korea; Department of Physiology, Yonsei University College of Medicine, Seoul 03722, Republic of Korea.
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Kwak MJ, Choi SJ, Cai WT, Cho BR, Han J, Park JW, Riecken LB, Morrison H, Choi SY, Kim WY, Kim JH. Manipulation of radixin phosphorylation in the nucleus accumbens core modulates risky choice behavior. Prog Neurobiol 2024; 242:102681. [PMID: 39437882 DOI: 10.1016/j.pneurobio.2024.102681] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2024] [Revised: 09/15/2024] [Accepted: 10/16/2024] [Indexed: 10/25/2024]
Abstract
Ezrin-Radixin-Moesin (ERM) proteins are actin-binding proteins that contribute to morphological changes in dendritic spines. Despite their significant role in regulating spine structure, the role of ERM proteins in the nucleus accumbnes (NAcc) is not well known, especially in in the context of risk-reward decision-making. Here, we measured the relationship between synaptic excitation and inhibition (E/I ratio) from medium spiny neurons in the NAcc core obtained in the rat after a rat gambling task (rGT). Then, after surgery of a phosphomimetic pseudo-active mutant form of radixin (Rdx-T564D) in the NAcc core, we examined its role in synaptic plasticity and the accompanying risk-choice behavior in rGT. We found that basal E/I ratio in the NAcc core was higher in risk-averse rats than risk-seeking rats. However, it was significantly reduced in risk-averse rats similar to that in risk-seeking rats in the presence of Rdx-T564D in the NAcc core. Furthermore, the head sizes of spines were shifted in risk-averse rats expressing Rdx-T564D in the NAcc core, similar to those observed in risk-seeking rats. The effects of Rdx-T564D in risk-averse rats were again manifested as behavioral changes, with reduced selection of optimal choices and increased selection of disadvantageous ones. In this study, we demonstrated that manipulation of radixin phosphorylation status in the NAcc core can alter glutamatergic synaptic transmission and spine structure at this site, as well as risk choice behaviors in the rGT. These novel findings illustrate that radixin in the NAcc core plays a significant role in determining risk preference during the rGT.
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Affiliation(s)
- Myung Ji Kwak
- Department of Physiology, Yonsei University College of Medicine, Seoul 03722, Republic of Korea; Department of Medical Sciences, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
| | - Su Jeong Choi
- Department of Physiology, Dental Research Institute, Seoul National University School of Dentistry, Seoul 03080, Republic of Korea
| | - Wen Ting Cai
- Department of Physiology, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
| | - Bo Ram Cho
- Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06519, USA
| | - Joonyeup Han
- Department of Physiology, Yonsei University College of Medicine, Seoul 03722, Republic of Korea; Department of Medical Sciences, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
| | - Jong Woo Park
- Department of Physiology, Yonsei University College of Medicine, Seoul 03722, Republic of Korea; Department of Medical Sciences, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
| | | | - Helen Morrison
- Leibniz Institute on Aging, Fritz Lipman Institute, Jena 07745, Germany
| | - Se-Young Choi
- Department of Physiology, Dental Research Institute, Seoul National University School of Dentistry, Seoul 03080, Republic of Korea.
| | - Wha Young Kim
- Department of Physiology, Yonsei University College of Medicine, Seoul 03722, Republic of Korea.
| | - Jeong-Hoon Kim
- Department of Physiology, Yonsei University College of Medicine, Seoul 03722, Republic of Korea; Department of Medical Sciences, Yonsei University College of Medicine, Seoul 03722, Republic of Korea.
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Ebrahimi MN, Banazadeh M, Alitaneh Z, Jaafari Suha A, Esmaeili A, Hasannejad-Asl B, Siahposht-Khachaki A, Hassanshahi A, Bagheri-Mohammadi S. The distribution of neurotransmitters in the brain circuitry: Mesolimbic pathway and addiction. Physiol Behav 2024; 284:114639. [PMID: 39004195 DOI: 10.1016/j.physbeh.2024.114639] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2024] [Revised: 07/08/2024] [Accepted: 07/10/2024] [Indexed: 07/16/2024]
Abstract
Understanding the central nervous system (CNS) circuitry and its different neurotransmitters that underlie reward is essential to improve treatment for many common health issues, such as addiction. Here, we concentrate on understanding how the mesolimbic circuitry and neurotransmitters are organized and function, and how drug exposure affects synaptic and structural changes in this circuitry. While the role of some reward circuits, like the cerebral dopamine (DA)/glutamate (Glu)/gamma aminobutyric acid (GABA)ergic pathways, in drug reward, is well known, new research using molecular-based methods has shown functional alterations throughout the reward circuitry that contribute to various aspects of addiction, including craving and relapse. A new understanding of the fundamental connections between brain regions as well as the molecular alterations within these particular microcircuits, such as neurotrophic factor and molecular signaling or distinct receptor function, that underlie synaptic and structural plasticity evoked by drugs of abuse has been made possible by the ability to observe and manipulate neuronal activity within specific cell types and circuits. It is exciting that these discoveries from preclinical animal research are now being applied in the clinic, where therapies for human drug dependence, such as deep brain stimulation and transcranial magnetic stimulation, are being tested. Therefore, this chapter seeks to summarize the current understanding of the important brain regions (especially, mesolimbic circuitry) and neurotransmitters implicated in drug-related behaviors and the molecular mechanisms that contribute to altered connectivity between these areas, with the postulation that increased knowledge of the plasticity within the drug reward circuit will lead to new and improved treatments for addiction.
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Affiliation(s)
- Mohammad Navid Ebrahimi
- Neuroscience Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran
| | - Mohammad Banazadeh
- Pharmaceutical Sciences and Cosmetic Products Research Center, Kerman University of Medical Sciences, Kerman, Iran
| | - Zahra Alitaneh
- Quantitative and System Biology, Department of Natural Sciences, University of California Merced, USA
| | - Ali Jaafari Suha
- Department of Physiology and Neurophysiology Research Center, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ali Esmaeili
- Student Research Committee, Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Behnam Hasannejad-Asl
- Department of Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti, University of Medical Sciences, Tehran, Iran
| | - Ali Siahposht-Khachaki
- Immunogenetics Research Center, Department of Physiology, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
| | - Amin Hassanshahi
- Department of Physiology, Bam University of Medical Sciences, Bam, Iran
| | - Saeid Bagheri-Mohammadi
- Department of Paramedicine, Amol School of Paramedical Sciences, Mazandaran University of Medical Sciences, Sari, Iran; Immunogenetics Research Center, Mazandaran University of Medical Sciences, Sari, Iran.
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Xie Q, Dasari R, Namba MD, Buck LA, Side CM, Park K, Jackson JG, Barker JM. Astrocytic Regulation of Cocaine Locomotor Sensitization in EcoHIV Infected Mice. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.09.04.611213. [PMID: 39282274 PMCID: PMC11398419 DOI: 10.1101/2024.09.04.611213] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/25/2024]
Abstract
Cocaine use disorder (CUD) is highly comorbid with HIV infection and worsens HIV outcomes. Preclinical research on the outcomes of HIV infection may yield crucial information on neurobehavioral changes resulting from chronic drug exposure in people living with HIV (PLWH). Repeated exposure to cocaine alters behavioral responses to cocaine. This includes development of cocaine locomotor sensitization - or increased locomotor responses to the same doses of cocaine - which depends on nucleus accumbens (NAc) neural plasticity. NAc astrocytes are key regulators of neural activity and plasticity, and their function can be impaired by cocaine exposure and HIV infection, thus implicating them as potential regulators of HIV-induced changes in behavioral response to cocaine. To characterize the effects of HIV infection on cocaine locomotor sensitization, we employed the EcoHIV mouse model to assess changes in locomotor responses after repeated cocaine (10mg/kg) exposure and challenge. EcoHIV infection potentiated expression of cocaine sensitization. We also identified EcoHIV-induced increases in expression of the astrocytic nuclear marker Sox9 selectively in the NAc core. To investigate whether modulation of NAc astrocytes could reverse EcoHIV-induced deficits, we employed a chemogenetic approach. We found that chemogenetic activation of NAc astrocyte Gq signaling attenuated EcoHIV-enhanced cocaine sensitization. We propose that HIV infection contributes to cocaine behavioral sensitization and induces adaptations in NAc astrocytes, while promoting NAc astrocytic Gq-signaling can recover EcoHIV-induced behavioral changes. These findings identify potential cellular substrates of disordered cocaine-driven behavior in the context of HIV infection and point toward strategies to reduce cocaine-related behavior in PLWH.
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Borland JM. The effects of different types of social interactions on the electrophysiology of neurons in the nucleus accumbens in rodents. Neurosci Biobehav Rev 2024; 164:105809. [PMID: 39004323 PMCID: PMC11771367 DOI: 10.1016/j.neubiorev.2024.105809] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2024] [Revised: 07/05/2024] [Accepted: 07/08/2024] [Indexed: 07/16/2024]
Abstract
BORLAND, J.M., The effects of different types of social interactions on the electrophysiology of neurons in the nucleus accumbens in rodents, NEUROSCI BIOBEH REV 21(1) XXX-XXX, 2024.-Sociality shapes an organisms' life. The nucleus accumbens is a critical brain region for mental health. In the following review, the effects of different types of social interactions on the physiology of neurons in the nucleus accumbens is synthesized. More specifically, the effects of sex behavior, aggression, social defeat, pair-bonding, play behavior, affiliative interactions, parental behaviors, the isolation from social interactions and maternal separation on measures of excitatory synaptic transmission, intracellular signaling and factors of transcription and translation in neurons in the nucleus accumbens in rodent models are reviewed. Similarities and differences in effects depending on the type of social interaction is then discussed. This review improves the understanding of the molecular and synaptic mechanisms of sociality.
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Yalçın B, Pomrenze MB, Malacon K, Drexler R, Rogers AE, Shamardani K, Chau IJ, Taylor KR, Ni L, Contreras-Esquivel D, Malenka RC, Monje M. Myelin plasticity in the ventral tegmental area is required for opioid reward. Nature 2024; 630:677-685. [PMID: 38839962 PMCID: PMC11186775 DOI: 10.1038/s41586-024-07525-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2023] [Accepted: 05/07/2024] [Indexed: 06/07/2024]
Abstract
All drugs of abuse induce long-lasting changes in synaptic transmission and neural circuit function that underlie substance-use disorders1,2. Another recently appreciated mechanism of neural circuit plasticity is mediated through activity-regulated changes in myelin that can tune circuit function and influence cognitive behaviour3-7. Here we explore the role of myelin plasticity in dopaminergic circuitry and reward learning. We demonstrate that dopaminergic neuronal activity-regulated myelin plasticity is a key modulator of dopaminergic circuit function and opioid reward. Oligodendroglial lineage cells respond to dopaminergic neuronal activity evoked by optogenetic stimulation of dopaminergic neurons, optogenetic inhibition of GABAergic neurons, or administration of morphine. These oligodendroglial changes are evident selectively within the ventral tegmental area but not along the axonal projections in the medial forebrain bundle nor within the target nucleus accumbens. Genetic blockade of oligodendrogenesis dampens dopamine release dynamics in nucleus accumbens and impairs behavioural conditioning to morphine. Taken together, these findings underscore a critical role for oligodendrogenesis in reward learning and identify dopaminergic neuronal activity-regulated myelin plasticity as an important circuit modification that is required for opioid reward.
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Affiliation(s)
- Belgin Yalçın
- Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, USA
| | - Matthew B Pomrenze
- Nancy Pritzker Laboratory, Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA
| | - Karen Malacon
- Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, USA
| | - Richard Drexler
- Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, USA
| | - Abigail E Rogers
- Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, USA
| | - Kiarash Shamardani
- Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, USA
| | - Isabelle J Chau
- Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, USA
| | - Kathryn R Taylor
- Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, USA
| | - Lijun Ni
- Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, USA
| | | | - Robert C Malenka
- Nancy Pritzker Laboratory, Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA
| | - Michelle Monje
- Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, USA.
- Howard Hughes Medical Institute, Stanford, CA, USA.
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Chapp AD, Nwakama CA, Jagtap PP, Phan CMH, Thomas MJ, Mermelstein PG. Fundamental Sex Differences in Cocaine-Induced Plasticity of Dopamine D1 Receptor- and D2 Receptor-Expressing Medium Spiny Neurons in the Mouse Nucleus Accumbens Shell. BIOLOGICAL PSYCHIATRY GLOBAL OPEN SCIENCE 2024; 4:100295. [PMID: 38533248 PMCID: PMC10963205 DOI: 10.1016/j.bpsgos.2024.100295] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2023] [Revised: 02/02/2024] [Accepted: 02/11/2024] [Indexed: 03/28/2024] Open
Abstract
Background Cocaine-induced plasticity in the nucleus accumbens shell of males occurs primarily in dopamine D1 receptor-expressing medium spiny neurons (D1R-MSNs), with little if any impact on dopamine D2 receptor-expressing medium spiny neurons (D2R-MSNs). In females, the effect of cocaine on accumbens shell D1R- and D2R-MSN neurophysiology has yet to be reported, nor have estrous cycle effects been accounted for. Methods We used a 5-day locomotor sensitization paradigm followed by a 10- to 14-day drug-free abstinence period. We then obtained ex vivo whole-cell recordings from fluorescently labeled D1R-MSNs and D2R-MSNs in the nucleus accumbens shell of male and female mice during estrus and diestrus. We examined accumbens shell neuronal excitability as well as miniature excitatory postsynaptic currents (mEPSCs). Results In females, we observed alterations in D1R-MSN excitability across the estrous cycle similar in magnitude to the effects of cocaine in males. Furthermore, cocaine shifted estrous cycle-dependent plasticity from intrinsic excitability changes in D1R-MSNs to D2R-MSNs. In males, cocaine treatment produced the anticipated drop in D1R-MSN excitability with no effect on D2R-MSN excitability. Cocaine increased mEPSC frequencies and amplitudes in D2R-MSNs from females in estrus and mEPSC amplitudes of D2R-MSNs from females in diestrus. In males, cocaine increased both D1R- and D2R-MSN mEPSC amplitudes with no effect on mEPSC frequencies. Conclusions Overall, while there are similar cocaine-induced disparities regarding the relative excitability of D1R-MSNs versus D2R-MSNs between the sexes, this is mediated through reduced D1R-MSN excitability in males, whereas it is due to heightened D2R-MSN excitability in females.
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Affiliation(s)
- Andrew D. Chapp
- Department of Neuroscience, University of Minnesota, Minneapolis, Minnesota
- Medical Discovery Team on Addiction, University of Minnesota, Minneapolis, Minnesota
| | - Chinonso A. Nwakama
- Department of Neuroscience, University of Minnesota, Minneapolis, Minnesota
- Medical Discovery Team on Addiction, University of Minnesota, Minneapolis, Minnesota
- Medical Scientist Training Program, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Pramit P. Jagtap
- Department of Neuroscience, University of Minnesota, Minneapolis, Minnesota
| | - Chau-Mi H. Phan
- Department of Neuroscience, University of Minnesota, Minneapolis, Minnesota
| | - Mark J. Thomas
- Department of Neuroscience, University of Minnesota, Minneapolis, Minnesota
- Medical Discovery Team on Addiction, University of Minnesota, Minneapolis, Minnesota
- Center for Neural Circuits in Addiction, University of Minnesota, Minneapolis, Minnesota
| | - Paul G. Mermelstein
- Department of Neuroscience, University of Minnesota, Minneapolis, Minnesota
- Medical Discovery Team on Addiction, University of Minnesota, Minneapolis, Minnesota
- Center for Neural Circuits in Addiction, University of Minnesota, Minneapolis, Minnesota
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Memos N, Avila JA, Rodriguez E, Serrano PA. Synaptic remodeling of GluA1 and GluA2 expression in the nucleus accumbens promotes susceptibility to cognitive deficits concomitant with downstream GSK3 β mediated neurotoxicity in female mice during abstinence from voluntary oral methamphetamine. ADDICTION NEUROSCIENCE 2023; 8:100112. [PMID: 37842014 PMCID: PMC10569060 DOI: 10.1016/j.addicn.2023.100112] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/17/2023]
Abstract
Stimulant-use disorders can present with long-term cognitive and mental health deficits. Little is known about the underlying molecular mechanisms perpetuating sex differences in cognitive and behavioral deficits in preclinical models of addiction to stimulants such as methamphetamine (MA). The current study investigated the neurochemical shifts underlying sex disparities in MA-induced working memory deficits and an addictive phenotype following abstinence from chronic MA abuse. We used our previously reported mouse model of voluntary oral methamphetamine administration (VOMA) consisting of an acquisition phase (days 1-14) characterized by escalating doses of MA and a binge phase (days 14-28) characterized by static doses. Female VOMA mice exhibited sustained MA consumption during the binge phase, demonstrating sex-specific vulnerabilities to the maintenance of MA addiction. The 8-arm radial maze was used to test spatial working memory performance following abstinence from VOMA. Results indicate working memory deficits correlated to higher MA consumption in females only. Hippocampal and accumbal tissue were collected and analyzed by immunoblotting. Female VOMA mice had decreased GluA1, but not GluA2, in the hippocampus, which may perpetuate synaptic destabilization and working memory deficits. Female-specific increases in GluA1 and p-GSK3β expression in accumbal tissue suggest vulnerability toward abstinence-induced drug craving and heightened downstream neurotoxicity. Our study reveals female-specific neurochemical shifts in hippocampal and accumbal AMPA receptor signaling following abstinence from chronic MA consumption that may perpetuate female susceptibility to MA-induced cognitive deficits. These data demonstrate a novel molecular pathway that would exacerbate memory deficits and perpetuate an addictive phenotype in female populations following MA abuse.
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Affiliation(s)
- Nicoletta Memos
- Department of Psychology, Hunter College, City University of New York, New York, NY, 10065, USA
- The Graduate Center of CUNY, New York, NY, 10016, USA
| | - Jorge A. Avila
- Undergraduate Research Center – Sciences, University of California, Los Angeles, CA 90095, USA
| | - Edgar Rodriguez
- Department of Psychology, Hunter College, City University of New York, New York, NY, 10065, USA
- The Graduate Center of CUNY, New York, NY, 10016, USA
| | - Peter A. Serrano
- Department of Psychology, Hunter College, City University of New York, New York, NY, 10065, USA
- The Graduate Center of CUNY, New York, NY, 10016, USA
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13
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Jazaeri SZ, Taghizadeh G, Babaei JF, Goudarzi S, Saadatmand P, Joghataei MT, Khanahmadi Z. Aquaporin 4 beyond a water channel; participation in motor, sensory, cognitive and psychological performances, a comprehensive review. Physiol Behav 2023; 271:114353. [PMID: 37714320 DOI: 10.1016/j.physbeh.2023.114353] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2023] [Revised: 08/15/2023] [Accepted: 09/13/2023] [Indexed: 09/17/2023]
Abstract
Aquaporin 4 (AQP4) is a protein highly expressed in the central nervous system (CNS) and peripheral nervous system (PNS) as well as various other organs, whose different sites of action indicate its importance in various functions. AQP4 has a variety of essential roles beyond water homeostasis. In this article, we have for the first time summarized different roles of AQP4 in motor and sensory functions, besides cognitive and psychological performances, and most importantly, possible physiological mechanisms by which AQP4 can exert its effects. Furthermore, we demonstrated that AQP4 participates in pathology of different neurological disorders, various effects depending on the disease type. Since neurological diseases involve a spectrum of dysfunctions and due to the difficulty of obtaining a treatment that can simultaneously affect these deficits, it is therefore suggested that future studies consider the role of this protein in different functional impairments related to neurological disorders simultaneously or separately by targeting AQP4 expression and/or polarity modulation.
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Affiliation(s)
- Seyede Zohreh Jazaeri
- Department of Neuroscience, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran; Division of Neuroscience, Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Ghorban Taghizadeh
- Department of Occupational Therapy, School of Rehabilitation Sciences, Iran University of Medical Sciences, Tehran, Iran.
| | - Javad Fahanik Babaei
- Electrophysiology Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Sepideh Goudarzi
- Experimental Medicine Research Center, Tehran University of medical Sciences, Tehran, Iran
| | - Pegah Saadatmand
- Department of Medical Physics, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Mohammad Taghi Joghataei
- Department of Neuroscience, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran; Division of Neuroscience, Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran; Department of Anatomy, School of Medicine, Iran University of Medical Sciences, Tehran, Iran; Department of Innovation in Medical Education, Faculty of Medicine, Ottawa University, Ottawa, Canada.
| | - Zohreh Khanahmadi
- Department of Occupational Therapy, School of Rehabilitation Services, Isfahan University of Medical Sciences, Isfahan, Iran
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14
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Catalfio AM, Fetterly TL, Nieto AM, Robinson TE, Ferrario CR. Cocaine-induced sensitization and glutamate plasticity in the nucleus accumbens core: effects of sex. Biol Sex Differ 2023; 14:41. [PMID: 37355656 PMCID: PMC10290362 DOI: 10.1186/s13293-023-00525-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2023] [Accepted: 06/12/2023] [Indexed: 06/26/2023] Open
Abstract
BACKGROUND The development and persistence of addiction is mediated in part by drug-induced alterations in nucleus accumbens (NAc) function. AMPA-type glutamate receptors (AMPARs) provide the main source of excitatory drive to the NAc and enhancements in transmission of calcium-permeable AMPARs (CP-AMPARs) mediate increased cue-triggered drug-seeking following prolonged withdrawal. Cocaine treatment regimens that result in psychomotor sensitization enhance subsequent drug-seeking and drug-taking behaviors. Furthermore, cocaine-induced locomotor sensitization followed by 14 days of withdrawal results in an increase in glutamatergic synaptic transmission. However, very few studies have examined cocaine-induced alterations in synaptic transmission of females or potential effects of experimenter-administered cocaine on NAc CP-AMPAR-mediated transmission in either sex. METHODS Male and female rats were given repeated systemic cocaine injections to induce psychomotor sensitization (15 mg/kg, i.p. 1 injection/day, 8 days). Controls received repeated saline (1 mL/kg, i.p). After 14-16 days of withdrawal brain slices were prepared and whole-cell patch-clamp approaches in the NAc core were used to measure spontaneous excitatory post-synaptic currents (sEPSC), paired pulse ratio, and CP-AMPAR transmission. Additional female rats from this same cohort were also given a challenge injection of cocaine at withdrawal day 14 to assess the expression of sensitization. RESULTS Repeated cocaine produced psychomotor sensitization in both sexes. In males this was accompanied by an increase in sEPSC frequency, but not amplitude, and there was no effect on the paired pulse ratio. Males treated with cocaine and saline had similar sensitivity to Naspm. In contrast, in females there were no significant differences between cocaine and saline groups on any measure, despite females showing robust psychomotor sensitization both during the induction and expression phase. CONCLUSIONS Overall, these data reveal striking sex differences in cocaine-induced NAc glutamate plasticity that accompany the induction of psychomotor sensitization. This suggests that the neural adaptations that contribute to sensitization vary by sex.
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Affiliation(s)
| | | | - Allison M. Nieto
- Pharmacology Department, University of Michigan, Ann Arbor, MI USA
- Neuroscience Graduate Program, University of California, Berkeley, CA USA
| | - Terry E. Robinson
- Psychology Department (Biopsychology Area), University of Michigan, Ann Arbor, MI USA
| | - Carrie R. Ferrario
- Pharmacology Department, University of Michigan, Ann Arbor, MI USA
- Psychology Department (Biopsychology Area), University of Michigan, Ann Arbor, MI USA
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15
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Jiang Y, Zou M, Wang Y, Wang Y. Nucleus accumbens in the pathogenesis of major depressive disorder: A brief review. Brain Res Bull 2023; 196:68-75. [PMID: 36889362 DOI: 10.1016/j.brainresbull.2023.03.004] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2022] [Revised: 02/16/2023] [Accepted: 03/05/2023] [Indexed: 03/08/2023]
Abstract
Major depressive disorder (MDD) is the most prevalent mental disorder characterized by anhedonia, loss of motivation, avolition, behavioral despair and cognitive abnormalities. Despite substantial advancements in the pathophysiology of MDD in recent years, the pathogenesis of this disorder is not fully understood. Meanwhile,the treatment of MDD with currently available antidepressants is inadequate, highlighting the urgent need for clarifying the pathophysiology of MDD and developing novel therapeutics. Extensive studies have demonstrated the involvement of nuclei such as the prefrontal cortex (PFC), hippocampus (HIP), nucleus accumbens (NAc), hypothalamus, etc., in MDD. NAc,a region critical for reward and motivation,dysregulation of its activity seems to be a hallmark of this mood disorder. In this paper, we present a review of NAc related circuits, cellular and molecular mechanisms underlying MDD and share an analysis of the gaps in current research and possible future research directions.
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Affiliation(s)
- Yajie Jiang
- Institute of Innovation and Applied Research in Chinese Medicine, Hunan University of Chinese Medicine, Changsha, China; Hunan Key Laboratory of Traditional Chinese Medicine Prevention & Treatment of Depressive Diseases, Changsha, China
| | - Manshu Zou
- Hunan Key Laboratory of Traditional Chinese Medicine Prevention & Treatment of Depressive Diseases, Changsha, China
| | - Yeqing Wang
- State Key Laboratory of Developmental Biology of Freshwater Fish, Hunan Provincial Key Laboratory of Animal Intestinal Function and Regulation, Laboratory of Animal Nutrition and Human Health, College of Life Sciences, Hunan Normal University, Changsha 410081, China
| | - Yuhong Wang
- Institute of Innovation and Applied Research in Chinese Medicine, Hunan University of Chinese Medicine, Changsha, China; Hunan Key Laboratory of Traditional Chinese Medicine Prevention & Treatment of Depressive Diseases, Changsha, China.
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16
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Schoenrock SA, Gagnon L, Olson A, Leonardo M, Philip VM, He H, Reinholdt LG, Sukoff Rizzo SJ, Jentsch JD, Chesler EJ, Tarantino LM. The collaborative cross strains and their founders vary widely in cocaine-induced behavioral sensitization. Front Behav Neurosci 2022; 16:886524. [PMID: 36275853 PMCID: PMC9580558 DOI: 10.3389/fnbeh.2022.886524] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Accepted: 08/01/2022] [Indexed: 07/25/2023] Open
Abstract
Cocaine use and overdose deaths attributed to cocaine have increased significantly in the United States in the last 10 years. Despite the prevalence of cocaine use disorder (CUD) and the personal and societal problems it presents, there are currently no approved pharmaceutical treatments. The absence of treatment options is due, in part, to our lack of knowledge about the etiology of CUDs. There is ample evidence that genetics plays a role in increasing CUD risk but thus far, very few risk genes have been identified in human studies. Genetic studies in mice have been extremely useful for identifying genetic loci and genes, but have been limited to very few genetic backgrounds, leaving substantial phenotypic, and genetic diversity unexplored. Herein we report the measurement of cocaine-induced behavioral sensitization using a 19-day protocol that captures baseline locomotor activity, initial locomotor response to an acute exposure to cocaine and locomotor sensitization across 5 exposures to the drug. These behaviors were measured in 51 genetically diverse Collaborative Cross (CC) strains along with their inbred founder strains. The CC was generated by crossing eight genetically diverse inbred strains such that each inbred CC strain has genetic contributions from each of the founder strains. Inbred CC mice are infinitely reproducible and provide a stable, yet diverse genetic platform on which to study the genetic architecture and genetic correlations among phenotypes. We have identified significant differences in cocaine locomotor sensitivity and behavioral sensitization across the panel of CC strains and their founders. We have established relationships among cocaine sensitization behaviors and identified extreme responding strains that can be used in future studies aimed at understanding the genetic, biological, and pharmacological mechanisms that drive addiction-related behaviors. Finally, we have determined that these behaviors exhibit relatively robust heritability making them amenable to future genetic mapping studies to identify addiction risk genes and genetic pathways that can be studied as potential targets for the development of novel therapeutics.
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Affiliation(s)
- Sarah A. Schoenrock
- Department of Genetics, School of Medicine, Chapel Hill, NC, United States
- Center for Systems Neurogenetics of Addiction, Bar Harbor, ME, United States
| | - Leona Gagnon
- Center for Systems Neurogenetics of Addiction, Bar Harbor, ME, United States
- The Jackson Laboratory, Bar Harbor, ME, United States
| | - Ashley Olson
- Center for Systems Neurogenetics of Addiction, Bar Harbor, ME, United States
- The Jackson Laboratory, Bar Harbor, ME, United States
| | - Michael Leonardo
- Center for Systems Neurogenetics of Addiction, Bar Harbor, ME, United States
- The Jackson Laboratory, Bar Harbor, ME, United States
| | - Vivek M. Philip
- Center for Systems Neurogenetics of Addiction, Bar Harbor, ME, United States
- The Jackson Laboratory, Bar Harbor, ME, United States
| | - Hao He
- Center for Systems Neurogenetics of Addiction, Bar Harbor, ME, United States
- The Jackson Laboratory, Bar Harbor, ME, United States
| | - Laura G. Reinholdt
- Center for Systems Neurogenetics of Addiction, Bar Harbor, ME, United States
- The Jackson Laboratory, Bar Harbor, ME, United States
| | - Stacey J. Sukoff Rizzo
- Center for Systems Neurogenetics of Addiction, Bar Harbor, ME, United States
- The Jackson Laboratory, Bar Harbor, ME, United States
- Department of Medicine, University of Pittsburgh, Pittsburgh, PA, United States
| | - James D. Jentsch
- Center for Systems Neurogenetics of Addiction, Bar Harbor, ME, United States
- Department of Psychology, Binghamton University, Binghamton, NY, United States
| | - Elissa J. Chesler
- Center for Systems Neurogenetics of Addiction, Bar Harbor, ME, United States
- The Jackson Laboratory, Bar Harbor, ME, United States
| | - Lisa M. Tarantino
- Department of Genetics, School of Medicine, Chapel Hill, NC, United States
- Center for Systems Neurogenetics of Addiction, Bar Harbor, ME, United States
- Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
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17
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Zuo CS, Davis KA, Lukas SE. Lower dACC glutamate in cannabis users during early phase abstinence. Neuropsychopharmacology 2022; 47:1969-1975. [PMID: 35484401 PMCID: PMC9485248 DOI: 10.1038/s41386-022-01321-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2021] [Revised: 03/10/2022] [Accepted: 03/31/2022] [Indexed: 11/08/2022]
Abstract
Glutamate plays an important role in continued use of and relapse to abused substances. However, its involvement in cannabis withdrawal is still unclear. We hypothesize that regional glutamate is associated with the cannabis withdrawal syndrome and recently examined possible association of glutamate with cannabis withdrawal, using magnetic resonance spectroscopy (MRS), in non-treatment-seeking cannabis users. We recruited 26 frequent cannabis users and 11 age-matched non-using controls. Of the 37, 20 users (8f/12m) and 10 controls (5f/5m) completed a verified 21-day abstinence protocol. Dorsal anterior cingulate cortex (dACC) glutamate and γ-amino butyric acid (GABA) were measured with proton MRS at baseline and on abstinent days 7 and 21 in conjunction with measures of cannabis withdrawal and craving (MCQ), sleep difficulties (PSQI) and mood state. We used ANOVA to examine group differences in glutamate and GABA from baseline through day 21 and used linear regression to evaluate correlations between intra-individual glutamate and withdrawal symptoms. We found that self-reported anxiety severity (HAMA) was correlated with urinary THC/Cr ratios at baseline (r = 0.768, p = 0.000076) and abstinent day 7 (r = 0.5636, p = 0.0097), dACC glutamate was significantly lower in the users compared with the controls from baseline through day 21 (F = 5.90, p = 0.022), changes in glutamate between baseline and abstinent day 21 had a significantly negative correlation with corresponding changes in craving (r = -0.72, p = 0.005) after adjusting for age, consumption of alcohol/cigarettes, sleep difficulties, and urinary THC levels. These findings provide preliminary evidence that dACC glutamate is associated with the cannabis withdrawal syndrome.
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Affiliation(s)
- Chun S Zuo
- McLean Imaging Center, McLean Hospital, Harvard Medical School, Belmont, MA, 02478, USA.
| | - Katherine A Davis
- McLean Imaging Center, McLean Hospital, Harvard Medical School, Belmont, MA, 02478, USA
| | - Scott E Lukas
- McLean Imaging Center, McLean Hospital, Harvard Medical School, Belmont, MA, 02478, USA
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18
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Jensen KL, Jensen SB, Madsen KL. A mechanistic overview of approaches for the treatment of psychostimulant dependence. Front Pharmacol 2022; 13:854176. [PMID: 36160447 PMCID: PMC9493975 DOI: 10.3389/fphar.2022.854176] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Accepted: 07/21/2022] [Indexed: 11/13/2022] Open
Abstract
Psychostimulant use disorder is a major health issue around the world with enormous individual, family-related and societal consequences, yet there are no effective pharmacological treatments available. In this review, a target-based overview of pharmacological treatments toward psychostimulant addiction will be presented. We will go through therapeutic approaches targeting different aspects of psychostimulant addiction with focus on three major areas; 1) drugs targeting signalling, and metabolism of the dopamine system, 2) drugs targeting either AMPA receptors or metabotropic glutamate receptors of the glutamate system and 3) drugs targeting the severe side-effects of quitting long-term psychostimulant use. For each of these major modes of intervention, findings from pre-clinical studies in rodents to clinical trials in humans will be listed, and future perspectives of the different treatment strategies as well as their potential side-effects will be discussed. Pharmaceuticals modulating the dopamine system, such as antipsychotics, DAT-inhibitors, and disulfiram, have shown some promising results. Cognitive enhancers have been found to increase aspects of behavioural control, and drugs targeting the glutamate system such as modulators of metabotropic glutamate receptors and AMPA receptors have provided interesting changes in relapse behaviour. Furthermore, CRF-antagonists directed toward alleviating the symptoms of the withdrawal stage have been examined with interesting resulting changes in behaviour. There are promising results investigating therapeutics for psychostimulant addiction, but further preclinical work and additional human studies with a more stratified patient selection are needed to prove sufficient evidence of efficacy and tolerability.
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19
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Zhao Y, Wang M, Hu K, Wang Q, Lou J, Fan L, Liu B. The development of cortical functional hierarchy is associated with the molecular organization of prenatal/postnatal periods. Cereb Cortex 2022; 33:4248-4261. [PMID: 36069939 DOI: 10.1093/cercor/bhac340] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2022] [Revised: 07/14/2022] [Accepted: 08/02/2022] [Indexed: 11/14/2022] Open
Abstract
The human cerebral cortex conforms to specific functional hierarchies facilitating information processing and higher-order cognition. Prior studies in adults have unveiled a dominant functional hierarchy spanning from sensorimotor regions to transmodal regions, which is also present in younger cohorts. However, how the functional hierarchy develops and the underlying molecular mechanisms remain to be investigated. Here, we set out to investigate the developmental patterns of the functional hierarchy for preschool children (#scans = 141, age = 2.41-6.90 years) using a parsimonious general linear model and the underlying biological mechanisms by combining the neuroimaging developmental pattern with two separate transcriptomic datasets (i.e. Allen Human Brain Atlas and BrainSpan Atlas). Our results indicated that transmodal regions were further segregated from sensorimotor regions and that such changes were potentially driven by two gene clusters with distinct enrichment profiles, namely prenatal gene cluster and postnatal gene cluster. Additionally, we found similar developmental profiles manifested in subsequent developmental periods by conducting identical analyses on the Human Connectome Projects in Development (#scans = 638, age = 5.58-21.92 years) and Philadelphia Neurodevelopment Cohort datasets (#scans = 795, age = 8-21 years), driven by concordant two gene clusters. Together, these findings illuminate a comprehensive developmental principle of the functional hierarchy and the underpinning molecular factors, and thus may shed light on the potential pathobiology of neurodevelopmental disorders.
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Affiliation(s)
- Yuxin Zhao
- Brainnetome Center and National Laboratory of Pattern Recognition, Institute of Automation, Chinese Academy of Sciences, Beijing 100190, China.,School of Artificial Intelligence, University of Chinese Academy of Sciences, Beijing 100049, China
| | - Meng Wang
- Brainnetome Center and National Laboratory of Pattern Recognition, Institute of Automation, Chinese Academy of Sciences, Beijing 100190, China.,School of Artificial Intelligence, University of Chinese Academy of Sciences, Beijing 100049, China
| | - Ke Hu
- Brainnetome Center and National Laboratory of Pattern Recognition, Institute of Automation, Chinese Academy of Sciences, Beijing 100190, China.,School of Artificial Intelligence, University of Chinese Academy of Sciences, Beijing 100049, China
| | - Qi Wang
- Brainnetome Center and National Laboratory of Pattern Recognition, Institute of Automation, Chinese Academy of Sciences, Beijing 100190, China.,School of Artificial Intelligence, University of Chinese Academy of Sciences, Beijing 100049, China
| | - Jing Lou
- State Key Laboratory of Cognitive Neuroscience and Learning, Beijing Normal University, Beijing 100875, China
| | - Lingzhong Fan
- Brainnetome Center and National Laboratory of Pattern Recognition, Institute of Automation, Chinese Academy of Sciences, Beijing 100190, China.,School of Artificial Intelligence, University of Chinese Academy of Sciences, Beijing 100049, China.,CAS Center for Excellence in Brain Science and Intelligence Technology, Institute of Automation, Chinese Academy of Sciences, Beijing 100190, China
| | - Bing Liu
- State Key Laboratory of Cognitive Neuroscience and Learning, Beijing Normal University, Beijing 100875, China.,Chinese Institute for Brain Research, Beijing 102206, China
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20
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Morgan C, Sáez-Briones P, Barra R, Reyes A, Zepeda-Morales K, Constandil L, Ríos M, Ramírez P, Burgos H, Hernández A. Prefrontal Cortical Control of Activity in Nucleus Accumbens Core Is Weakened by High-Fat Diet and Prevented by Co-Treatment with N-Acetylcysteine: Implications for the Development of Obesity. Int J Mol Sci 2022; 23:10089. [PMID: 36077493 PMCID: PMC9456091 DOI: 10.3390/ijms231710089] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2022] [Revised: 08/31/2022] [Accepted: 08/31/2022] [Indexed: 12/05/2022] Open
Abstract
A loss of neuroplastic control on nucleus accumbens (NAc) neuronal activity exerted by the medial prefrontal cortex (mPFC) through long-term depression (LTD) is involved in triggering drug-seeking behavior and relapse on several substances of abuse due to impaired glutamate homeostasis in tripartite synapses of the nucleus accumbens (NAc) core. To test whether this maladaptive neuroplastic mechanism underlies the addiction-like behavior induced in young mice by a high-fat diet (HFD), we utilized 28-days-old male mice fed HFD ad-libitum over 2 weeks, followed by 5 days of HFD abstinence. Control groups were fed a regular diet. HFD fed mice showed increased ΔFosB levels in the NAc core region, whereas LTD triggered from the mPFC became suppressed. Interestingly, LTD suppression was prevented by an i.p. injection of 100 mg/kg N-acetylcysteine 2.5 h before inducing LTD from the mPFC. In addition, excessive weight gain due to HFD feeding was diminished by adding 2mg/mL N-acetylcysteine in drinking water. Those results show a loss of neuroplastic mPFC control over NAc core activity induced by HFD consumption in young subjects. In conclusion, ad libitum consumption of HFD can lead to neuroplastic changes an addiction-like behavior that can be prevented by N-acetylcysteine, helping to decrease the rate of excessive weight gain.
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Affiliation(s)
- Carlos Morgan
- Laboratorio de Neurofarmacología y Comportamiento, Escuela de Medicina, Facultad de Ciencias Médicas, Universidad de Santiago de Chile, Santiago 9170022, Chile
| | - Patricio Sáez-Briones
- Laboratorio de Neurofarmacología y Comportamiento, Escuela de Medicina, Facultad de Ciencias Médicas, Universidad de Santiago de Chile, Santiago 9170022, Chile
| | - Rafael Barra
- Centro de Investigación Biomédica y Aplicada (CIBAP), Escuela de Medicina, Facultad de Ciencias Médicas, Universidad de Santiago de Chile, Santiago 9170022, Chile
| | - Andrea Reyes
- Laboratorio de Neurobiología, Facultad de Química y Biología, Universidad de Santiago de Chile, Santiago 9170022, Chile
| | - Katherine Zepeda-Morales
- Laboratorio de Neurobiología, Facultad de Química y Biología, Universidad de Santiago de Chile, Santiago 9170022, Chile
| | - Luis Constandil
- Laboratorio de Neurobiología, Facultad de Química y Biología, Universidad de Santiago de Chile, Santiago 9170022, Chile
| | - Miguel Ríos
- Laboratorio de Neurobiología, Facultad de Química y Biología, Universidad de Santiago de Chile, Santiago 9170022, Chile
| | - Paulina Ramírez
- Bluestone Center for Clinical Research, Department of Oral and Maxillofacial Surgery, New York University College of Dentistry, New York, NY 10010, USA
| | - Héctor Burgos
- Escuela de Psicología, Facultad de Medicina y Ciencias de la Salud, Universidad Mayor, Santiago 7570008, Chile
| | - Alejandro Hernández
- Laboratorio de Neurobiología, Facultad de Química y Biología, Universidad de Santiago de Chile, Santiago 9170022, Chile
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21
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Li S, Zhang XQ, Liu CC, Wang ZY, Lu GY, Shen HW, Wu N, Li J, Li F. IRAS/Nischarin modulates morphine reward by glutamate receptor activation in the nucleus accumbens of mouse brain. Biomed Pharmacother 2022; 153:113346. [DOI: 10.1016/j.biopha.2022.113346] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2022] [Revised: 06/22/2022] [Accepted: 06/24/2022] [Indexed: 11/02/2022] Open
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22
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Yuan A, King N, Kharas N, Yang P, Dafny N. The effect of environment on cross-sensitization between methylphenidate and amphetamine in female rats. Physiol Behav 2022; 252:113845. [PMID: 35594929 DOI: 10.1016/j.physbeh.2022.113845] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2021] [Revised: 04/22/2022] [Accepted: 05/15/2022] [Indexed: 11/17/2022]
Abstract
Methylphenidate (MPD) and amphetamine (AMP) are both psychostimulants that are often used to treat behavioral disorders. More recently, it has also been increasingly used illicitly for recreation as well as to improve intellectual performance. Many factors such as age, gender, genetic background, and environment govern the development of behavioral sensitization to MPD and cross-sensitization with other drugs, which are experimental behavioral markers indicating potential of substance dependence and abuse. This study examines the effects of the environment and age when MPD was exposed in adulthood alone as well as in adolescence into adulthood on cross-sensitization with AMP in female SD rats by randomizing animals to either receive the drug in a home cage or a test cage during adolescence, adulthood, or both. In a 34 day experiment, 16 groups of animals starting in adolescence were treated with saline on experimental day one (ED1), followed by a 6 day (ED2-ED7) treatment with either saline, 0.6 mg/kg AMP, 0.6, 2.5, or 10.0 mg/kg MPD. Experimental groups were then subject to a 3-day washout period (ED8-ED10) and then a retreatment with the respective drug on ED11 in adolescence (P-38 to P-49). Experiments continued in the same animal groups now in adulthood (P-60) with a saline treatment (ED1), followed by the same sequence of treatments in adolescence (ED2-ED11;P-61 to P-69). A rechallenge with the same AMP or MPD dose was performed on ED11 (P-70) followed by a single exposure to 0.6 mg/kg AMP on ED12 (P-71) to assess for cross sensitization between MPD and AMP. Animals treated with MPD in both adolescence and adulthood and in the last experimental day of AMP (ED12) showed higher intensity of cross-sensitivity between MPD and AMP as compared to animals treated with MPD only in adulthood. AMP and MPD treatment in adolescence and into adulthood in the home or test cage resulted in significantly higher responses to the drug as compared to those treated only in adulthood. Overall, we conclude that environmental alteration and adolescent exposure to MPD appeared to increase the risk of cross-sensitization to AMP in female SD rats i.e, using MPD in adolescence may increase the probability of becoming dependent on drugs of abuse. This further indicates that age, sex, and environment all influence the response to MPD and AMP, and further work is needed to elucidate the risks associated with MPD and AMP use.
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Affiliation(s)
- Anthony Yuan
- Department of Neurobiology and Anatomy, University of Texas Health at the McGovern Medical School, 6431 Fannin Street, MSB 7.208, Houston, TX 77030, United States
| | - Nicholas King
- Department of Neurobiology and Anatomy, University of Texas Health at the McGovern Medical School, 6431 Fannin Street, MSB 7.208, Houston, TX 77030, United States
| | - Natasha Kharas
- Department of Neurobiology and Anatomy, University of Texas Health at the McGovern Medical School, 6431 Fannin Street, MSB 7.208, Houston, TX 77030, United States
| | - Pamela Yang
- Department of Neurobiology and Anatomy, University of Texas Health at the McGovern Medical School, 6431 Fannin Street, MSB 7.208, Houston, TX 77030, United States
| | - Nachum Dafny
- Department of Neurobiology and Anatomy, University of Texas Health at the McGovern Medical School, 6431 Fannin Street, MSB 7.208, Houston, TX 77030, United States.
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Prefrontal Cortex Response to Prenatal Insult and Postnatal Opioid Exposure. Genes (Basel) 2022; 13:genes13081371. [PMID: 36011282 PMCID: PMC9407090 DOI: 10.3390/genes13081371] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Revised: 07/27/2022] [Accepted: 07/28/2022] [Indexed: 12/11/2022] Open
Abstract
The influence of proinflammatory challenges, such as maternal immune activation (MIA) or postnatal exposure to drugs of abuse, on brain molecular pathways has been reported. On the other hand, the simultaneous effects of MIA and drugs of abuse have been less studied and sometimes offered inconsistent results. The effects of morphine exposure on a pig model of viral-elicited MIA were characterized in the prefrontal cortex of males and females using RNA-sequencing and gene network analysis. Interacting and main effects of morphine, MIA, and sex were detected in approximately 2000 genes (false discovery rate-adjusted p-value < 0.05). Among the enriched molecular categories (false discovery rate-adjusted p-value < 0.05 and −1.5 > normalized enrichment score > 1.5) were the cell adhesion molecule pathways associated with inflammation and neuronal development and the long-term depression pathway associated with synaptic strength. Gene networks that integrate gene connectivity and expression profiles displayed the impact of morphine-by-MIA interaction effects on the pathways. The cell adhesion molecules and long-term depression networks presented an antagonistic effect between morphine and MIA. The differential expression between the double-challenged group and the baseline saline-treated Controls was less extreme than the individual challenges. The previous findings advance the knowledge about the effects of prenatal MIA and postnatal morphine exposure on the prefrontal cortex pathways.
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Inbar K, Levi LA, Kupchik YM. Cocaine induces input and cell-type-specific synaptic plasticity in ventral pallidum-projecting nucleus accumbens medium spiny neurons. Neuropsychopharmacology 2022; 47:1461-1472. [PMID: 35121830 PMCID: PMC9205871 DOI: 10.1038/s41386-022-01285-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2021] [Revised: 01/23/2022] [Accepted: 01/24/2022] [Indexed: 11/09/2022]
Abstract
Cocaine use and abstinence induce long-term synaptic alterations in the excitatory input to nucleus accumbens (NAc) medium spiny neurons (MSNs). The NAc regulates reward-related behaviors through two parallel projections to the ventral pallidum (VP)-originating in D1 or D2-expressing MSNs (D1-MSNs→VP; D2-MSNs→VP). The activity of these projections depends on their excitatory synaptic inputs, but it is not known whether and how abstinence from cocaine affects the excitatory transmission to D1-MSNs→VP and D2-MSNs→VP. Here we examined different forms of cocaine-induced synaptic plasticity in the inputs from the basolateral amygdala (BLA) and medial prefrontal cortex (mPFC) to NAc D1-MSNs→VP and putative D2-MSNs→VP (pD2-MSNs→VP) in the core and shell subcompartments of the NAc. We used the whole-cell patch-clamp technique to record excitatory postsynaptic currents from D1-tdTomato mice injected with ChR2 in either the BLA or the mPFC and retrograde tracer (RetroBeads) in the VP. We found that cocaine conditioned place preference (CPP) followed by abstinence potentiated the excitatory input from the BLA and mPFC to both D1-MSNs→VP and pD2-MSNs→VP. Interestingly, while the strengthening of the inputs to D1-MSNs→VP was of postsynaptic origin and manifested as increased AMPA to NMDA ratio, in pD2-MSNs→VP plasticity was predominantly presynaptic and was detected as changes in the paired-pulse ratio and coefficient of variation. Lastly, some of the changes were sex-specific. Overall our data show that abstinence from cocaine changes the excitatory inputs to both D1-MSNs→VP and pD2-MSNs→VP but with different mechanisms. This may help understand how circuits converging into the VP change after cocaine exposure.
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Affiliation(s)
- Kineret Inbar
- grid.9619.70000 0004 1937 0538Department of Medical Neurobiology, Faculty of Medicine, The Institute for Medical Research Israel-Canada (IMRIC), The Hebrew University of Jerusalem, Jerusalem, 9112102 Israel
| | - Liran A. Levi
- grid.9619.70000 0004 1937 0538Department of Medical Neurobiology, Faculty of Medicine, The Institute for Medical Research Israel-Canada (IMRIC), The Hebrew University of Jerusalem, Jerusalem, 9112102 Israel
| | - Yonatan M. Kupchik
- grid.9619.70000 0004 1937 0538Department of Medical Neurobiology, Faculty of Medicine, The Institute for Medical Research Israel-Canada (IMRIC), The Hebrew University of Jerusalem, Jerusalem, 9112102 Israel
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25
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Fleming W, Lee J, Briones BA, Bolkan SS, Witten IB. Cholinergic interneurons mediate cocaine extinction in male mice through plasticity across medium spiny neuron subtypes. Cell Rep 2022; 39:110874. [PMID: 35649378 PMCID: PMC9196889 DOI: 10.1016/j.celrep.2022.110874] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2021] [Revised: 03/07/2022] [Accepted: 05/05/2022] [Indexed: 11/28/2022] Open
Abstract
Cholinergic interneurons (ChINs) in the nucleus accumbens (NAc) have been implicated in the extinction of drug associations, as well as related plasticity in medium spiny neurons (MSNs). However, since most previous work relied on artificial manipulations, whether endogenous acetylcholine signaling relates to drug associations is unclear. Moreover, despite great interest in the opposing effects of dopamine on MSN subtypes, whether ChIN-mediated effects vary by MSN subtype is also unclear. Here, we find that high endogenous acetylcholine event frequency correlates with greater extinction of cocaine-context associations across male mice. Additionally, extinction is associated with a weakening of glutamatergic synapses across MSN subtypes. Manipulating ChIN activity bidirectionally controls both the rate of extinction and the associated plasticity at MSNs. Our findings indicate that NAc ChINs mediate drug-context extinction by reducing glutamatergic synaptic strength across MSN subtypes, and that natural variation in acetylcholine signaling may contribute to individual differences in extinction.
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Affiliation(s)
- Weston Fleming
- Princeton Neuroscience Institute, Princeton, NJ 08544, USA
| | - Junuk Lee
- Princeton Neuroscience Institute, Princeton, NJ 08544, USA
| | - Brandy A Briones
- Princeton Neuroscience Institute, Princeton, NJ 08544, USA; Department of Psychology, Princeton University, Princeton, NJ 08544, USA
| | - Scott S Bolkan
- Princeton Neuroscience Institute, Princeton, NJ 08544, USA
| | - Ilana B Witten
- Princeton Neuroscience Institute, Princeton, NJ 08544, USA; Department of Psychology, Princeton University, Princeton, NJ 08544, USA.
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26
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Chronic facial inflammatory pain-induced anxiety is associated with bilateral deactivation of the rostral anterior cingulate cortex. Brain Res Bull 2022; 184:88-98. [PMID: 35339627 DOI: 10.1016/j.brainresbull.2022.03.012] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2022] [Revised: 03/15/2022] [Accepted: 03/21/2022] [Indexed: 11/22/2022]
Abstract
Patients with chronic pain, especially orofacial pain, often suffer from affective disorders, including anxiety. Previous studies largely focused on the role of the caudal anterior cingulate cortex (cACC) in affective responses to pain, long-term potentiation (LTP) in cACC being thought to mediate the interaction between anxiety and chronic pain. But recent evidence indicates that the rostral ACC (rACC), too, is implicated in processing affective pain. However, whether such processing is associated with neuronal and/or synaptic plasticity is still unknown. We addressed this issue in a chronic facial inflammatory pain model (complete Freund's adjuvant model) in rats, by combining behavior, Fos protein immunochemistry and ex vivo intracellular recordings in rACC slices prepared from these animals. Facial mechanical allodynia occurs immediately after CFA injection, peaks at post-injection day 3 and progressively recovers until post-injection days 10-11, whereas anxiety is delayed, being present at post-injection day 10, when sensory hypersensitivity is relieved, but, notably, not at post-injection day 3. Fos expression reveals that neuronal activity follows a bi-phasic time course in bilateral rACC: first enhanced at post-injection day 3, it gets strongly depressed at post-injection day 10. Ex vivo recordings from lamina V pyramidal neurons, the rACC projecting neurons, show that both their intrinsic excitability and excitatory synaptic inputs have undergone long-term depression (LTD) at post-injection day 10. Thus chronic pain processing is associated with dynamic changes in rACC activity: first enhanced and subsequently decreased, at the time of anxiety-like behavior. Chronic pain-induced anxiety might thus result from a rACC deactivation-cACC hyperactivation interplay.
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27
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Hunger dampens a nucleus accumbens circuit to drive persistent food seeking. Curr Biol 2022; 32:1689-1702.e4. [DOI: 10.1016/j.cub.2022.02.034] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Revised: 01/11/2022] [Accepted: 02/09/2022] [Indexed: 02/07/2023]
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28
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Addiction-induced plasticity in underlying neural circuits. Neurol Sci 2022; 43:1605-1615. [DOI: 10.1007/s10072-021-05778-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2021] [Accepted: 11/20/2021] [Indexed: 10/19/2022]
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29
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Robison AJ, Nestler EJ. ΔFOSB: A Potentially Druggable Master Orchestrator of Activity-Dependent Gene Expression. ACS Chem Neurosci 2022; 13:296-307. [PMID: 35020364 PMCID: PMC8879420 DOI: 10.1021/acschemneuro.1c00723] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
ΔFOSB is a uniquely stable member of the FOS family of immediate early gene AP1 transcription factors. Its accumulation in specific cell types and tissues in response to a range of chronic stimuli is associated with biological phenomena as diverse as memory formation, drug addiction, stress resilience, and immune cell activity. Causal connections between ΔFOSB expression and the physiological and behavioral sequelae of chronic stimuli have been established in rodent and, in some cases, primate models for numerous healthy and pathological states with such preclinical observations often supported by human data demonstrating tissue-specific ΔFOSB expression associated with several specific syndromes. However, the viability of ΔFOSB as a target for therapeutic intervention might be questioned over presumptive concerns of side effects given its expression in such a wide range of cell types and circumstances. Here, we summarize numerous insights from the past three decades of research into ΔFOSB structure, function, mechanisms of induction, and regulation of target genes that support its potential as a druggable target. We pay particular attention to the potential for targeting distinct ΔFOSB isoforms or distinct ΔFOSB-containing multiprotein complexes to achieve cell type or tissue specificity to overcome off-target concerns. We also cover critical gaps in knowledge that currently limit the exploitation of ΔFOSB's therapeutic possibilities and how they may be addressed. Finally, we summarize both current and potential future strategies for generating small molecules or genetic tools for the manipulation of ΔFOSB in the clinic.
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Affiliation(s)
- Alfred J Robison
- Department of Physiology, Michigan State University, East Lansing, Michigan 48824, United States
| | - Eric J Nestler
- Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, United States
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30
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Manz KM, Coleman BC, Jameson AN, Ghose DG, Patel S, Grueter BA. Cocaine restricts nucleus accumbens feedforward drive through a monoamine-independent mechanism. Neuropsychopharmacology 2022; 47:652-663. [PMID: 34545194 PMCID: PMC8782870 DOI: 10.1038/s41386-021-01167-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/23/2021] [Revised: 08/23/2021] [Accepted: 08/24/2021] [Indexed: 02/08/2023]
Abstract
Parvalbumin-expressing fast-spiking interneurons (PV-INs) within feedforward microcircuits in the nucleus accumbens (NAc) coordinate goal-directed motivational behavior. Feedforward inhibition of medium spiny projection neurons (MSNs) is initiated by glutamatergic input from corticolimbic brain structures. While corticolimbic synapses onto MSNs are targeted by the psychostimulant, cocaine, it remains unknown whether cocaine also exerts acute neuromodulatory actions at collateralizing synapses onto PV-INs. Using whole-cell patch-clamp electrophysiology, optogenetics, and pharmacological tools in transgenic reporter mice, we found that cocaine decreases thalamocortical glutamatergic drive onto PV-INs by engaging a monoamine-independent mechanism. This mechanism relies on postsynaptic sigma-1 (σ1) activity, leading to the mobilization of intracellular Ca2+ stores that trigger retrograde endocannabinoid signaling at presynaptic type-1 cannabinoid receptors (CB1R). Cocaine-evoked CB1R activity occludes the expression of CB1R-dependent long-term depression (LTD) at this synaptic locus. These findings provide evidence that acute cocaine exposure targets feedforward microcircuits in the NAc and extend existing models of cocaine action on mesolimbic reward circuits.
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Affiliation(s)
- Kevin M Manz
- Medical Scientist Training Program, Vanderbilt University, Nashville, TN, USA
- Vanderbilt Brain Institute, Vanderbilt University, Nashville, TN, USA
- Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, TN, USA
| | | | - Alexis N Jameson
- Vanderbilt Brain Institute, Vanderbilt University, Nashville, TN, USA
| | - Dipanwita G Ghose
- Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Sachin Patel
- Vanderbilt Brain Institute, Vanderbilt University, Nashville, TN, USA
- Department of Psychiatry, Vanderbilt University Medical Center, Nashville, TN, USA
- Vanderbilt Center for Addiction Research, Vanderbilt University, Nashville, TN, USA
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA
| | - Brad A Grueter
- Vanderbilt Brain Institute, Vanderbilt University, Nashville, TN, USA.
- Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, TN, USA.
- Department of Pharmacology, Vanderbilt University, Nashville, TN, USA.
- Department of Psychiatry, Vanderbilt University Medical Center, Nashville, TN, USA.
- Vanderbilt Center for Addiction Research, Vanderbilt University, Nashville, TN, USA.
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA.
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31
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Jing PB, Chen XH, Lu HJ, Gao YJ, Wu XB. Enhanced function of NR2C/2D-containing NMDA receptor in the nucleus accumbens contributes to peripheral nerve injury-induced neuropathic pain and depression in mice. Mol Pain 2022; 18:17448069211053255. [PMID: 35057644 PMCID: PMC8785348 DOI: 10.1177/17448069211053255] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023] Open
Abstract
N-methyl-d-aspartate receptors (NMDARs) dysfunction in the nucleus accumbens (NAc) participates in regulating many neurological and psychiatric disorders such as drug addiction, chronic pain, and depression. NMDARs are heterotetrameric complexes generally composed of two NR1 and two NR2 subunits (NR2A, NR2B, NR2C and NR2D). Much attention has been focused on the role of NR2A and NR2B-containing NMDARs in a variety of neurological disorders; however, the function of NR2C/2D subunits at NAc in chronic pain remains unknown. In this study, spinal nerve ligation (SNL) induced a persistent sensory abnormity and depressive-like behavior. The whole-cell patch clamp recording on medium spiny neurons (MSNs) in the NAc showed that the amplitude of NMDAR-mediated excitatory postsynaptic currents (EPSCs) was significantly increased when membrane potential held at −40 to 0 mV in mice after 14 days of SNL operation. In addition, selective inhibition of NR2C/2D-containing NMDARs with PPDA caused a larger decrease on peak amplitude of NMDAR-EPSCs in SNL than that in sham-operated mice. Appling of selective potentiator of NR2C/2D, CIQ, markedly enhanced the evoked NMDAR-EPSCs in SNL-operated mice, but no change in sham-operated mice. Finally, intra-NAc injection of PPDA significantly attenuated SNL-induced mechanical allodynia and depressive-like behavior. These results for the first time showed that the functional change of NR2C/2D subunits-containing NMDARs in the NAc might contribute to the sensory and affective components in neuropathic pain.
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Affiliation(s)
- Peng-Bo Jing
- Institute of Pain Medicine and Special Environmental Medicine, Nantong University, Nantong, Jiangsu, China
| | - Xiao-Hong Chen
- Department of Anesthesiology, Tumor Hospital Affiliated to Nantong University and Nantong Tumor Hospital, Nantong, Jiangsu, China
| | - Huan-Jun Lu
- Institute of Pain Medicine and Special Environmental Medicine, Nantong University, Nantong, Jiangsu, China
| | - Yong-Jing Gao
- Institute of Pain Medicine and Special Environmental Medicine, Nantong University, Nantong, Jiangsu, China
- Co-innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu, China
| | - Xiao-Bo Wu
- Institute of Pain Medicine and Special Environmental Medicine, Nantong University, Nantong, Jiangsu, China
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32
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Li Y, Wei S, Liu Q, Gong Q, Zhang Q, Zheng T, Yong Z, Chen F, Lawrence AJ, Liang J. Mu-opioid receptors in septum mediate the development of behavioural sensitization to a single morphine exposure in male rats. Addict Biol 2022; 27:e13066. [PMID: 34030217 DOI: 10.1111/adb.13066] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2021] [Revised: 05/01/2021] [Accepted: 05/17/2021] [Indexed: 12/14/2022]
Abstract
Behavioural sensitization (BS) is characterized by enhanced psychomotor responses to a dose of substance of abuse after prior repeated exposure. We previously reported that BS can be induced by a single injection of morphine in rats, whereas septal nuclei are specifically involved in the development phase of BS. Here, we demonstrated that intra-LS or intra-MS microinjections also incubated BS to a systemic morphine injection in a cross-sensitization fashion, whereas inactivation of either subdivision of septal nuclei (LS: lateral septum; MS: medial septum) can negate this ability of morphine. Then, non-selective (naloxone) and selective (μ-, δ- and κ-)opioid receptor antagonists were directly delivered into LS or MS, respectively, ahead of a morphine microinjection, whereas only μ-opioid receptors in both LS and MS play indispensable roles in mediating the BS development. Finally, there was a pronounced elevation in the levels of the monoamines (i.e. dopamine, homovanillic acid, 5-hydroxytryptamine and 5-hydroxyindoleacetic acid) in the septum, 8 h after a morphine injection detected with a HPLC-ECD method, suggesting that dopaminergi and serotoninergic systems are implicated in the BS formation. Our studies demonstrated that septal nuclei critically participate in the BS development. Essentially, μ- instead of δ- or κ-opioid receptors in LS and MS mediate sensitization to opiates.
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Affiliation(s)
- Yu‐Ling Li
- Department of Pharmacology, School of Basic Medical Sciences Peking University Beijing China
- Department of Pharmacy, East Hospital Tongji University School of Medicine Shanghai China
| | - Shoupeng Wei
- Department of Pharmacology, School of Basic Medical Sciences Peking University Beijing China
- The Seventh Affiliated Hospital Sun Yat‐sen University Shenzhen China
| | - Qing Liu
- Department of Pharmacology, School of Basic Medical Sciences Peking University Beijing China
| | - Qi Gong
- Department of Pharmacology, School of Basic Medical Sciences Peking University Beijing China
| | - Qing‐Jie Zhang
- Department of Molecular and Cellular Pharmacology, School of Pharmaceutical Sciences Peking University Beijing China
| | - Tian‐Ge Zheng
- Department of Molecular and Cellular Pharmacology, School of Pharmaceutical Sciences Peking University Beijing China
| | - Zheng Yong
- Beijing Institute of Pharmacology and Toxicology Academy of Military Medical Sciences Beijing China
| | - Feng Chen
- The Florey Institute of Neuroscience and Mental Health University of Melbourne Parkville Victoria Australia
| | - Andrew J. Lawrence
- The Florey Institute of Neuroscience and Mental Health University of Melbourne Parkville Victoria Australia
| | - Jian‐Hui Liang
- Department of Molecular and Cellular Pharmacology, School of Pharmaceutical Sciences Peking University Beijing China
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33
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Vadakkan KI. Framework for internal sensation of pleasure using constraints from disparate findings in nucleus accumbens. World J Psychiatry 2021; 11:681-695. [PMID: 34733636 PMCID: PMC8546768 DOI: 10.5498/wjp.v11.i10.681] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2021] [Revised: 06/27/2021] [Accepted: 09/02/2021] [Indexed: 02/06/2023] Open
Abstract
It is necessary to find a mechanism that generates first-person inner sensation of pleasure to understand what causes addiction and associated behaviour by drugs of abuse. The actual mechanism is expected to explain several disparate findings in nucleus accumbens (NAc), a brain region associated with pleasure, in an interconnected manner. Previously, it was possible to derive a mechanism for natural learning and explain: (1) Generation of inner sensation of memory using changes generated by learning; and (2) Long-term potentiation as an experimental delayed scaled-up change by the same mechanism that occur during natural learning. By extending these findings and by using disparate third person observations in NAc from several studies, present work provides a framework of a mechanism that generates internal sensation of pleasure that can provide interconnected explanations for: (1) Ability to induce robust long-term depression (LTD) in NAc from naïve animals; (2) Impaired ability to induce LTD in “addicted” state; (3) Attenuation of postsynaptic potentials by cocaine; and (4) Reduced firing of medium spiny neurons in response to cocaine or dopamine. Findings made by this work are testable.
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Hu J, Liu J, Liu Y, Wu X, Zhuang K, Chen Q, Yang W, Xie P, Qiu J, Wei D. Dysfunction of the anterior and intermediate hippocampal functional network in major depressive disorders across the adult lifespan. Biol Psychol 2021; 165:108192. [PMID: 34555480 DOI: 10.1016/j.biopsycho.2021.108192] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2021] [Revised: 09/09/2021] [Accepted: 09/13/2021] [Indexed: 11/27/2022]
Abstract
Accumulating evidence indicates that structural and functional abnormalities in hippocampal formation are linked to major depressive disorder (MDD). However, the resting-state functional connectivity (RSFC) of hippocampal subfields in MDD remains unclear. This cross-sectional study aimed to investigate the RSFC of hippocampal subfields in a large sample of MDD patients. The results revealed that patients with MDD showed lower RSFC between the right anterior hippocampus and the insula, and the RSFC was inversely correlated with anxiety symptoms of depression. Depressed patients also showed decreased RSFC between the bilateral intermediate hippocampus and left nucleus accumbens (NAcc), and the hippocampus-NAcc circuit was negatively correlated with core symptoms of depression. The functional connectivity between the right anterior hippocampus and left postcentral gyrus increased with ageing in MDD patients compared with healthy controls. These findings suggest that the functional network of hippocampal subfields may underlie anxiety and core depression symptoms.
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Affiliation(s)
- Jun Hu
- Faculty of Psychology, Southwest University, Chongqing 400715, China; Key Laboratory of Cognition and Personality (Ministry of Education), Southwest University, Chongqing 400715, China
| | - Jiahui Liu
- Faculty of Psychology, Southwest University, Chongqing 400715, China; Key Laboratory of Cognition and Personality (Ministry of Education), Southwest University, Chongqing 400715, China
| | - Yu Liu
- Faculty of Psychology, Southwest University, Chongqing 400715, China; Key Laboratory of Cognition and Personality (Ministry of Education), Southwest University, Chongqing 400715, China
| | - Xianran Wu
- Faculty of Psychology, Southwest University, Chongqing 400715, China; Key Laboratory of Cognition and Personality (Ministry of Education), Southwest University, Chongqing 400715, China
| | - Kaixiang Zhuang
- Faculty of Psychology, Southwest University, Chongqing 400715, China; Key Laboratory of Cognition and Personality (Ministry of Education), Southwest University, Chongqing 400715, China
| | - Qunlin Chen
- Faculty of Psychology, Southwest University, Chongqing 400715, China; Key Laboratory of Cognition and Personality (Ministry of Education), Southwest University, Chongqing 400715, China
| | - Wenjing Yang
- Faculty of Psychology, Southwest University, Chongqing 400715, China; Key Laboratory of Cognition and Personality (Ministry of Education), Southwest University, Chongqing 400715, China
| | - Peng Xie
- Institute of Neuroscience, Chongqing Medical University, Chongqing, China; Chongqing Key Laboratory of Neurobiology, Chongqing, China; Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Jiang Qiu
- Faculty of Psychology, Southwest University, Chongqing 400715, China; Key Laboratory of Cognition and Personality (Ministry of Education), Southwest University, Chongqing 400715, China.
| | - Dongtao Wei
- Faculty of Psychology, Southwest University, Chongqing 400715, China; Key Laboratory of Cognition and Personality (Ministry of Education), Southwest University, Chongqing 400715, China.
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35
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Cheron J, Kerchove d'Exaerde AD. Drug addiction: from bench to bedside. Transl Psychiatry 2021; 11:424. [PMID: 34385417 PMCID: PMC8361217 DOI: 10.1038/s41398-021-01542-0] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2021] [Revised: 07/14/2021] [Accepted: 07/23/2021] [Indexed: 02/06/2023] Open
Abstract
Drug addiction is responsible for millions of deaths per year around the world. Still, its management as a chronic disease is shadowed by misconceptions from the general public. Indeed, drug consumers are often labelled as "weak", "immoral" or "depraved". Consequently, drug addiction is often perceived as an individual problem and not societal. In technical terms, drug addiction is defined as a chronic, relapsing disease resulting from sustained effects of drugs on the brain. Through a better characterisation of the cerebral circuits involved, and the long-term modifications of the brain induced by addictive drugs administrations, first, we might be able to change the way the general public see the patient who is suffering from drug addiction, and second, we might be able to find new treatments to normalise the altered brain homeostasis. In this review, we synthetise the contribution of fundamental research to the understanding drug addiction and its contribution to potential novel therapeutics. Mostly based on drug-induced modifications of synaptic plasticity and epigenetic mechanisms (and their behavioural correlates) and after demonstration of their reversibility, we tried to highlight promising therapeutics. We also underline the specific temporal dynamics and psychosocial aspects of this complex psychiatric disease adding parameters to be considered in clinical trials and paving the way to test new therapeutic venues.
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Affiliation(s)
- Julian Cheron
- Laboratory of Neurophysiology, ULB Neuroscience Institute, Université Libre de Bruxelles (ULB), Brussels, B-1070, Belgium
| | - Alban de Kerchove d'Exaerde
- Laboratory of Neurophysiology, ULB Neuroscience Institute, Université Libre de Bruxelles (ULB), Brussels, B-1070, Belgium.
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Caveolin-1 Expression in the Dorsal Striatum Drives Methamphetamine Addiction-Like Behavior. Int J Mol Sci 2021; 22:ijms22158219. [PMID: 34360984 PMCID: PMC8348638 DOI: 10.3390/ijms22158219] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2021] [Revised: 07/20/2021] [Accepted: 07/22/2021] [Indexed: 11/17/2022] Open
Abstract
Dopamine D1 receptor (D1R) function is regulated by membrane/lipid raft-resident protein caveolin-1 (Cav1). We examined whether altered expression of Cav1 in the dorsal striatum would affect self-administration of methamphetamine, an indirect agonist at the D1Rs. A lentiviral construct expressing Cav1 (LV-Cav1) or containing a short hairpin RNA against Cav1 (LV-shCav1) was used to overexpress or knock down Cav1 expression respectively, in the dorsal striatum. Under a fixed-ratio schedule, LV-Cav1 enhanced and LV-shCav1 reduced responding for methamphetamine in an extended access paradigm compared to LV-GFP controls. LV-Cav1 and LV-shCav1 also produced an upward and downward shift in a dose–response paradigm, generating a drug vulnerable/resistant phenotype. LV-Cav1 and LV-shCav1 did not alter responding for sucrose. Under a progressive-ratio schedule, LV-shCav1 generally reduced positive-reinforcing effects of methamphetamine and sucrose as seen by reduced breakpoints. Western blotting confirmed enhanced Cav1 expression in LV-Cav1 rats and reduced Cav1 expression in LV-shCav1 rats. Electrophysiological findings in LV-GFP rats demonstrated an absence of high-frequency stimulation (HFS)-induced long-term potentiation (LTP) in the dorsal striatum after extended access methamphetamine self-administration, indicating methamphetamine-induced occlusion of plasticity. LV-Cav1 prevented methamphetamine-induced plasticity via increasing phosphorylation of calcium calmodulin kinase II, suggesting a mechanism for addiction vulnerability. LV-shCav1 produced a marked deficit in the ability of HFS to produce LTP and, therefore, extended access methamphetamine was unable to alter striatal plasticity, indicating a mechanism for resistance to addiction-like behavior. Our results demonstrate that Cav1 expression and knockdown driven striatal plasticity assist with modulating addiction to drug and nondrug rewards, and inspire new strategies to reduce psychostimulant addiction.
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Lafferty CK, Christinck TD, Britt JP. All-optical approaches to studying psychiatric disease. Methods 2021; 203:46-55. [PMID: 34314828 DOI: 10.1016/j.ymeth.2021.07.007] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2021] [Revised: 07/20/2021] [Accepted: 07/22/2021] [Indexed: 11/17/2022] Open
Abstract
Improvements in all-optical means of monitoring and manipulating neural activity have generated new ways of studying psychiatric disease. The combination of calcium imaging techniques with optogenetics to concurrently record and manipulate neural activity has been used to create new disease models that link distinct circuit abnormalities to specific disease dimensions. These approaches represent a new path towards the development of more effective treatments, as they allow researchers to identify circuit manipulations that normalize pathological network activity. In this review we highlight the utility of all-optical approaches to generate new psychiatric disease models where the specific circuit abnormalities associated with disease symptomology can be assessed in vivo and in response to manipulations designed to normalize disease states. We then outline the principles underlying all-optical interrogations of neural circuits and discuss practical considerations for experimental design.
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Affiliation(s)
- Christopher K Lafferty
- Department of Psychology, McGill University, Montreal, QC, Canada; Center for Studies in Behavioral Neurobiology, Concordia University, Montreal, QC, Canada
| | - Thomas D Christinck
- Center for Studies in Behavioral Neurobiology, Concordia University, Montreal, QC, Canada; Integrated Program in Neuroscience, McGill University, Montreal, QC, Canada
| | - Jonathan P Britt
- Department of Psychology, McGill University, Montreal, QC, Canada; Center for Studies in Behavioral Neurobiology, Concordia University, Montreal, QC, Canada; Integrated Program in Neuroscience, McGill University, Montreal, QC, Canada.
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Optogenetically-inspired neuromodulation: Translating basic discoveries into therapeutic strategies. INTERNATIONAL REVIEW OF NEUROBIOLOGY 2021; 159:187-219. [PMID: 34446246 DOI: 10.1016/bs.irn.2021.06.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Optogenetic tools allow for the selective activation, inhibition or modulation of genetically-defined neural circuits with incredible temporal precision. Over the past decade, application of these tools in preclinical models of psychiatric disease has advanced our understanding the neural circuit basis of maladaptive behaviors in these disorders. Despite their power as an investigational tool, optogenetics cannot yet be applied in the clinical for the treatment of neurological and psychiatric disorders. To date, deep brain stimulation (DBS) is the only clinical treatment that can be used to achieve circuit-specific neuromodulation in the context of psychiatric. Despite its increasing clinical indications, the mechanisms underlying the therapeutic effects of DBS for psychiatric disorders are poorly understood, which makes optimization difficult. We discuss the variety of optogenetic tools available for preclinical research, and how these tools have been leveraged to reverse-engineer the mechanisms underlying DBS for movement and compulsive disorders. We review studies that have used optogenetics to induce plasticity within defined basal ganglia circuits, to alter neural circuit function and evaluate the corresponding effects on motor and compulsive behaviors. While not immediately applicable to patient populations, the translational power of optogenetics is in inspiring novel DBS protocols by providing a rationale for targeting defined neural circuits to ameliorate specific behavioral symptoms, and by establishing optimal stimulation paradigms that could selectively compensate for pathological synaptic plasticity within these defined neural circuits.
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Knouse MC, Briand LA. Behavioral sex differences in cocaine and opioid use disorders: The role of gonadal hormones. Neurosci Biobehav Rev 2021; 128:358-366. [PMID: 34214512 DOI: 10.1016/j.neubiorev.2021.06.038] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Revised: 05/20/2021] [Accepted: 06/27/2021] [Indexed: 11/20/2022]
Abstract
Females are more vulnerable than males to many aspects of cocaine use disorder. This vulnerability also translates to opioid use disorder, with females exhibiting stronger behavioral responses than males to drugs such as heroin and morphine. While there is evidence for many overlapping neural mechanisms underlying cocaine and opioid abuse, there is also a breadth of evidence indicating divergent effects of the drugs on synaptic plasticity. This makes it unclear whether the behavioral sex differences seen in substance use disorder across different drugs of abuse rely on the same mechanisms. Ovarian hormones have consistently been implicated as drivers of the behavioral sex differences in cocaine taking and seeking. While there are far fewer studies on the role of ovarian hormones in opioid use disorder, the existing data suggest that ovarian hormones may not drive these behavioral effects in the same manner as in cocaine use disorder. This review highlights evidence that behavioral sex differences in substance use disorder might be driven by different mechanisms depending on drug class.
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Affiliation(s)
| | - Lisa A Briand
- Department of Psychology, Temple University, United States; Neuroscience Program, Temple University, United States.
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40
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Chen APF, Chen L, Kim TA, Xiong Q. Integrating the Roles of Midbrain Dopamine Circuits in Behavior and Neuropsychiatric Disease. Biomedicines 2021; 9:biomedicines9060647. [PMID: 34200134 PMCID: PMC8228225 DOI: 10.3390/biomedicines9060647] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Revised: 06/01/2021] [Accepted: 06/03/2021] [Indexed: 01/11/2023] Open
Abstract
Dopamine (DA) is a behaviorally and clinically diverse neuromodulator that controls CNS function. DA plays major roles in many behaviors including locomotion, learning, habit formation, perception, and memory processing. Reflecting this, DA dysregulation produces a wide variety of cognitive symptoms seen in neuropsychiatric diseases such as Parkinson’s, Schizophrenia, addiction, and Alzheimer’s disease. Here, we review recent advances in the DA systems neuroscience field and explore the advancing hypothesis that DA’s behavioral function is linked to disease deficits in a neural circuit-dependent manner. We survey different brain areas including the basal ganglia’s dorsomedial/dorsolateral striatum, the ventral striatum, the auditory striatum, and the hippocampus in rodent models. Each of these regions have different reported functions and, correspondingly, DA’s reflecting role in each of these regions also has support for being different. We then focus on DA dysregulation states in Parkinson’s disease, addiction, and Alzheimer’s Disease, emphasizing how these afflictions are linked to different DA pathways. We draw upon ideas such as selective vulnerability and region-dependent physiology. These bodies of work suggest that different channels of DA may be dysregulated in different sets of disease. While these are great advances, the fine and definitive segregation of such pathways in behavior and disease remains to be seen. Future studies will be required to define DA’s necessity and contribution to the functional plasticity of different striatal regions.
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Affiliation(s)
- Allen PF Chen
- Department of Neurobiology and Behavior, Renaissance School of Medicine at Stony Brook University, Stony Brook, NY 11794, USA; (A.P.C.); (L.C.); (T.A.K.)
- Medical Scientist Training Program, Renaissance School of Medicine at Stony Brook University, Stony Brook, NY 11794, USA
| | - Lu Chen
- Department of Neurobiology and Behavior, Renaissance School of Medicine at Stony Brook University, Stony Brook, NY 11794, USA; (A.P.C.); (L.C.); (T.A.K.)
| | - Thomas A. Kim
- Department of Neurobiology and Behavior, Renaissance School of Medicine at Stony Brook University, Stony Brook, NY 11794, USA; (A.P.C.); (L.C.); (T.A.K.)
- Medical Scientist Training Program, Renaissance School of Medicine at Stony Brook University, Stony Brook, NY 11794, USA
| | - Qiaojie Xiong
- Department of Neurobiology and Behavior, Renaissance School of Medicine at Stony Brook University, Stony Brook, NY 11794, USA; (A.P.C.); (L.C.); (T.A.K.)
- Correspondence:
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CCL2/CCR2 Contributes to the Altered Excitatory-inhibitory Synaptic Balance in the Nucleus Accumbens Shell Following Peripheral Nerve Injury-induced Neuropathic Pain. Neurosci Bull 2021; 37:921-933. [PMID: 34003466 DOI: 10.1007/s12264-021-00697-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2020] [Accepted: 02/10/2021] [Indexed: 12/12/2022] Open
Abstract
The medium spiny neurons (MSNs) in the nucleus accumbens (NAc) integrate excitatory and inhibitory synaptic inputs and gate motivational and emotional behavior output. Here we report that the relative intensity of excitatory and inhibitory synaptic inputs to MSNs of the NAc shell was decreased in mice with neuropathic pain induced by spinal nerve ligation (SNL). SNL increased the frequency, but not the amplitude of spontaneous inhibitory postsynaptic currents (sIPSCs), and decreased both the frequency and amplitude of spontaneous excitatory postsynaptic currents (sEPSCs) in the MSNs. SNL also decreased the paired-pulse ratio (PPR) of evoked IPSCs but increased the PPR of evoked EPSCs. Moreover, acute bath application of C-C motif chemokine ligand 2 (CCL2) increased the frequency and amplitude of sIPSCs and sEPSCs in the MSNs, and especially strengthened the amplitude of N-methyl-D-aspartate receptor (NMDAR)-mediated miniature EPSCs. Further Ccl2 overexpression in the NAc in vivo decreased the peak amplitude of the sEPSC/sIPSC ratio. Finally, Ccr2 knock-down improved the impaired induction of NMDAR-dependent long-term depression (LTD) in the NAc after SNL. These results suggest that CCL2/CCR2 signaling plays a role in the integration of excitatory/inhibitory synaptic transmission and leads to an increase of the LTD induction threshold at the synapses of MSNs during neuropathic pain.
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Rigo F, Filošević A, Petrović M, Jović K, Andretić Waldowski R. Locomotor sensitization modulates voluntary self-administration of methamphetamine in Drosophila melanogaster. Addict Biol 2021; 26:e12963. [PMID: 32833318 DOI: 10.1111/adb.12963] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2020] [Revised: 07/01/2020] [Accepted: 08/10/2020] [Indexed: 12/25/2022]
Abstract
As complexities of addictive behaviors cannot be fully captured in laboratory studies, scientists use simple addiction-associated phenotypes and measure them in laboratory animals. Locomotor sensitization, characterized by an increased behavioral response to the same dose of the drug, has been extensively used to elucidate the genetic basis and molecular mechanisms of neuronal plasticity. However, to what extent it contributes to the development of addiction is not completely clear. We tested if the development of locomotor sensitization to methamphetamine affects voluntary self-administration, and vice versa, in order to investigate how two drug-associated phenotypes influence one another. In our study, we used the genetically tractable model organism, Drosophila melanogaster, and quantified locomotor sensitization and voluntary self-administration to methamphetamine using behavioral tests that were developed and adapted in our laboratory. We show that flies express robust locomotor sensitization to the second dose of volatilized methamphetamine, which significantly lowers preferential self-administration of methamphetamine. Naive flies preferentially self-administer food with methamphetamine over plain food. Exposing flies to volatilized methamphetamine after voluntary self-administration abolishes locomotor sensitization. We tested period null (per01 ) mutant flies and showed that they do not develop locomotor sensitization, nor do they show preferential self-administration of methamphetamine. Our results suggest that there may be partially overlapping neural circuitry that regulates the expression of locomotor sensitization and preferential self-administration to methamphetamine and that this circuitry requires a functional per gene.
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Affiliation(s)
- Franka Rigo
- Department of Biotechnology University of Rijeka Rijeka Croatia
| | - Ana Filošević
- Department of Biotechnology University of Rijeka Rijeka Croatia
| | - Milan Petrović
- Department of Informatics University of Rijeka Rijeka Croatia
| | - Katarina Jović
- Faculty of Health and Medical Sciences University of Surrey Guildford UK
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Wu CM, Lai TW. Microglia depletion by PLX3397 has no effect on cocaine-induced behavioral sensitization in male mice. Brain Res 2021; 1761:147391. [PMID: 33639199 DOI: 10.1016/j.brainres.2021.147391] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2020] [Revised: 02/21/2021] [Accepted: 02/22/2021] [Indexed: 12/11/2022]
Abstract
Cocaine and other addictive drugs are known to stimulate microglia, and microglia in turn have been shown to play roles in both the development and mitigation of drug dependence. For instance, cocaine can directly bind to surface receptors on microglia and trigger their release of interleukin-1β, which promotes addictive behaviors; however, cocaine also indirectly stimulates microglia by elevating dopamine, which causes microglia to impair long-lasting neuronal changes related to cocaine use. The seemingly opposing roles of microglia beg the question of what the net effect of microglial presence is on cocaine-induced behavioral changes. Here, we depleted microglia from the mouse brain by treating mice with PLX3397 and subjected the mice to cocaine-induced behavioral sensitization, a model for studying long-lasting neuronal changes associated with drugs of abuse. Although cocaine treatment had little effect on microglial abundance, PLX3397 treatment dramatically decreased the number of microglia in the nucleus accumbens and hippocampus in control mice and in mice subjected to cocaine sensitization. Importantly, loss of microglia did not appear to affect either the acute locomotor response to cocaine treatment or sensitization after repeated doses of cocaine. In conclusion, while our data do not contradict previous findings indicating that different microglial-derived factors can have seemingly opposite effects on behaviors associated with cocaine use, they suggest that microglia do not have a net effect on cocaine-induced long-lasting behavioral changes.
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Affiliation(s)
- Ching Mei Wu
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan
| | - Ted Weita Lai
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan; Drug Development Center, China Medical University, Taichung, Taiwan; Translational Medicine Research Center, China Medical University Hospital, Taichung, Taiwan.
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44
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Friend LN, Wu B, Edwards JG. Acute cocaine exposure occludes long-term depression in ventral tegmental area GABA neurons. Neurochem Int 2021; 145:105002. [PMID: 33617930 DOI: 10.1016/j.neuint.2021.105002] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2020] [Revised: 01/21/2021] [Accepted: 02/16/2021] [Indexed: 10/22/2022]
Abstract
The ventral tegmental area (VTA) in the midbrain is essential in incentive salience of reward behavior. Drugs of abuse increase midbrain dopamine cell activity and/or dopamine levels, and can alter endogenous VTA glutamate plasticity, leading to addiction or dependence. VTA dopamine cells are regulated by local inhibitory GABA cells, which exhibit a form of pre-synaptic cannabinoid receptor 1-dependent long-term depression of their glutamatergic inputs. Our current aim was to determine cocaine's influence on VTA GABA cell glutamate plasticity and circuity. Using whole cell voltage-clamp electrophysiology in VTA slices of GAD67-GFP knock-in mice, we recorded excitatory inputs on VTA GABA cells. Acute and chronic injections of cocaine were sufficient to occlude long-term depression. The plasticity could be reversed to the naïve state however, as long-term depression was again observed following a 7-day abstinence from acute cocaine exposure. Furthermore, chronic cocaine decreased AMPA/NMDA ratios at glutamate synapses onto VTA GABA cells, compared to vehicle injection controls, the opposite change noted in dopamine cells. Collectively, our data suggest the cellular mechanism of cocaine-mediated synaptic modification that may result in dependence/withdrawal could involve changes in glutamate input to VTA GABA circuitry in addition to VTA dopamine cells. Therefore VTA GABA cells may also play a role, possibly in a synergistic manner with the dopamine circuit, in cocaine-induced changes to the VTA reward pathway than previously known.
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Affiliation(s)
- Lindsey N Friend
- Brigham Young University, Neuroscience Center, Provo, UT, 84602, USA
| | - Bridget Wu
- Brigham Young University, Department of Physiology and Developmental Biology, Provo, UT, 84602, USA
| | - Jeffrey G Edwards
- Brigham Young University, Department of Physiology and Developmental Biology, Provo, UT, 84602, USA; Brigham Young University, Neuroscience Center, Provo, UT, 84602, USA.
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45
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Chapp AD, Mermelstein PG, Thomas MJ. The ethanol metabolite acetic acid activates mouse nucleus accumbens shell medium spiny neurons. J Neurophysiol 2021; 125:620-627. [PMID: 33405999 DOI: 10.1152/jn.00659.2020] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Although ethanol consumption leads to an array of neurophysiological alterations involving the neural circuits for reward, the underlying mechanisms remain unclear. Acetic acid is a major metabolite of ethanol with high bioactivity and potentially significant pharmacological importance in regulating brain function. Yet, the impact of acetic acid on reward circuit function has not been well explored. Given the rewarding properties associated with ethanol consumption, we investigated the acute effects of ethanol and/or acetic acid on the neurophysiological function of medium spiny neurons of the nucleus accumbens shell, a key node in the mammalian reward circuit. We find that acetic acid, but not ethanol, provided a rapid and robust boost in neuronal excitability at physiologically relevant concentrations, whereas both compounds enhanced glutamatergic synaptic activity. These effects were consistent across both sexes in C57BL/6J mice. Overall, our data suggest acetic acid is a promising candidate mediator for ethanol effects on mood and motivation that deserves further investigation.NEW & NOTEWORTHY Ethanol consumption disrupts many neurophysiological processes leading to alterations in behavior and physiological function. The possible involvement of acetic acid, produced via ethanol metabolism, has been insufficiently explored. Here, we demonstrate that acetic acid contributes to rapid neurophysiological alterations in the accumbens shell. These findings raise the interesting possibility that ethanol may serve as a prodrug-generating acetic acid as a metabolite-that may influence ethanol consumption-associated behaviors and physiological responses by altering neurophysiological function.
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Affiliation(s)
- Andrew D Chapp
- Department of Neuroscience, University of Minnesota, Minneapolis, Minnesota.,Medical Discovery Team on Addiction, University of Minnesota, Minneapolis, Minnesota
| | - Paul G Mermelstein
- Department of Neuroscience, University of Minnesota, Minneapolis, Minnesota.,Medical Discovery Team on Addiction, University of Minnesota, Minneapolis, Minnesota
| | - Mark J Thomas
- Department of Neuroscience, University of Minnesota, Minneapolis, Minnesota.,Medical Discovery Team on Addiction, University of Minnesota, Minneapolis, Minnesota
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46
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Li J, Zhu L, Su H, Liu D, Yan Z, Ni T, Wei H, Goh EL, Chen T. Regulation of miR-128 in the nucleus accumbens affects methamphetamine-induced behavioral sensitization by modulating proteins involved in neuroplasticity. Addict Biol 2021; 26:e12881. [PMID: 32058631 DOI: 10.1111/adb.12881] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2019] [Revised: 12/12/2019] [Accepted: 01/17/2020] [Indexed: 01/09/2023]
Abstract
Methamphetamine (METH) -induced behavioral sensitization depends on long-term neuroplasticity in the mesolimbic dopamine system, especially in the nucleus accumbens (NAc). miR-128, a brain enriched miRNA, was found to have abilities in regulating neuronal excitability and formation of fear-extinction memory. Here, we aim to identify the role of miR-128 on METH-induced locomotor sensitization of male mice. We identified a significant increase of miR-128 in the NAc of mice upon repeated-intermittent METH exposure but not acute METH administration. Microinjection of adeno-associated virus (AAV)-miR-128 over-expression and inhibition constructs into the NAc of mice resulted in enhanced METH-induced locomotor sensitization and attenuated effects of METH respectively. Isobaric tags for relative and absolute quantification (iTRAQ) technology and ingenuity pathway analysis (IPA) were carried out to uncover the potential molecular mechanisms underlying miR-128-regulated METH sensitization. Differentially expressed proteins, including 25 potential targets for miR-128 were annotated in regulatory pathways that modulate dendritic spines, synaptic transmission and neuritogenesis. Of which, Arf6, Cpeb3 and Nlgn1, were found to be participating in miR-128-regulated METH sensitization. Consistently, METH-induced abnormal changes of Arf6, Cpeb3 and Nlgn1 in the NAc of mice were also detected by qPCR and validated by western blot analysis. Thus, miR-128 may contribute to METH sensitization through controlling neuroplasticity. Our study suggested miR-128 was an important regulator of METH- induced sensitization and also provided the potential molecular networks of miR-128 in regulating METH-induced sensitization.
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Affiliation(s)
- Jiaqi Li
- College of Forensic Medicine Xi'an Jiaotong University Health Science Center Xi'an Shaanxi 710061 China
- The Key Laboratory of Health Ministry for Forensic Medicine, Xi'an Jiaotong University Shaanxi 710061 China
| | - Li Zhu
- College of Forensic Medicine Xi'an Jiaotong University Health Science Center Xi'an Shaanxi 710061 China
- The Key Laboratory of Health Ministry for Forensic Medicine, Xi'an Jiaotong University Shaanxi 710061 China
| | - Hang Su
- College of Forensic Medicine Xi'an Jiaotong University Health Science Center Xi'an Shaanxi 710061 China
- The Key Laboratory of Health Ministry for Forensic Medicine, Xi'an Jiaotong University Shaanxi 710061 China
| | - Dan Liu
- College of Forensic Medicine Xi'an Jiaotong University Health Science Center Xi'an Shaanxi 710061 China
- The Key Laboratory of Health Ministry for Forensic Medicine, Xi'an Jiaotong University Shaanxi 710061 China
| | - Zhilan Yan
- College of Forensic Medicine Xi'an Jiaotong University Health Science Center Xi'an Shaanxi 710061 China
- The Key Laboratory of Health Ministry for Forensic Medicine, Xi'an Jiaotong University Shaanxi 710061 China
| | - Tong Ni
- College of Forensic Medicine Xi'an Jiaotong University Health Science Center Xi'an Shaanxi 710061 China
- The Key Laboratory of Health Ministry for Forensic Medicine, Xi'an Jiaotong University Shaanxi 710061 China
| | - Han Wei
- College of Forensic Medicine Xi'an Jiaotong University Health Science Center Xi'an Shaanxi 710061 China
- The Key Laboratory of Health Ministry for Forensic Medicine, Xi'an Jiaotong University Shaanxi 710061 China
| | - Eyleen L.K. Goh
- Department of Research National Neuroscience Institute Singapore 308433
- Neuroscience and Mental Health Faculty, Lee Kong China School of Medicine Nanyang Technological University Singapore 308232
| | - Teng Chen
- College of Forensic Medicine Xi'an Jiaotong University Health Science Center Xi'an Shaanxi 710061 China
- The Key Laboratory of Health Ministry for Forensic Medicine, Xi'an Jiaotong University Shaanxi 710061 China
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47
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Thompson BL, Oscar-Berman M, Kaplan GB. Opioid-induced structural and functional plasticity of medium-spiny neurons in the nucleus accumbens. Neurosci Biobehav Rev 2021; 120:417-430. [PMID: 33152423 PMCID: PMC7855607 DOI: 10.1016/j.neubiorev.2020.10.015] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2020] [Revised: 10/16/2020] [Accepted: 10/20/2020] [Indexed: 12/21/2022]
Abstract
Opioid Use Disorder (OUD) is a chronic relapsing clinical condition with tremendous morbidity and mortality that frequently persists, despite treatment, due to an individual's underlying psychological, neurobiological, and genetic vulnerabilities. Evidence suggests that these vulnerabilities may have neurochemical, cellular, and molecular bases. Key neuroplastic events within the mesocorticolimbic system that emerge through chronic exposure to opioids may have a determinative influence on behavioral symptoms associated with OUD. In particular, structural and functional alterations in the dendritic spines of medium spiny neurons (MSNs) within the nucleus accumbens (NAc) and its dopaminergic projections from the ventral tegmental area (VTA) are believed to facilitate these behavioral sequelae. Additionally, glutamatergic neurons from the prefrontal cortex, the basolateral amygdala, the hippocampus, and the thalamus project to these same MSNs, providing an enriched target for synaptic plasticity. Here, we review literature related to neuroadaptations in NAc MSNs from dopaminergic and glutamatergic pathways in OUD. We also describe new findings related to transcriptional, epigenetic, and molecular mechanisms in MSN plasticity in the different stages of OUD.
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Affiliation(s)
- Benjamin L Thompson
- Department of Radiology & Biomedical Imaging, Yale School of Medicine, New Haven, CT, 06520, USA; Research Service, VA Boston Healthcare System, 150 South Huntington Avenue, Boston, MA 02130, USA.
| | - Marlene Oscar-Berman
- Research Service, VA Boston Healthcare System, 150 South Huntington Avenue, Boston, MA 02130, USA; Department of Anatomy & Neurobiology, Boston University School of Medicine, 72 East Concord Street, Boston, MA, 02118, USA; Department of Psychiatry, Boston University School of Medicine, 720 Harrison Avenue, Boston, MA, 02118, USA; Department of Neurology, Boston University School of Medicine, Boston University Medical Center, 80 East Concord Street, Boston, MA 02118, USA.
| | - Gary B Kaplan
- Department of Psychiatry, Boston University School of Medicine, 720 Harrison Avenue, Boston, MA, 02118, USA; Mental Health Service, VA Boston Healthcare System, 940 Belmont Street, Brockton, MA, 02301, USA; Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, 72 East Concord Street, Boston, MA, 02118, USA.
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48
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Metaplasticity in the Ventral Pallidum as a Potential Marker for the Propensity to Gain Weight in Chronic High-Calorie Diet. J Neurosci 2020; 40:9725-9735. [PMID: 33199503 DOI: 10.1523/jneurosci.1809-20.2020] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2020] [Revised: 10/03/2020] [Accepted: 10/06/2020] [Indexed: 12/30/2022] Open
Abstract
A major driver of obesity is the increasing palatability of processed foods. Although reward circuits promote the consumption of palatable food, their involvement in obesity remains unclear. The ventral pallidum (VP) is a key hub in the reward system that encodes the hedonic aspects of palatable food consumption and participates in various proposed feeding circuits. However, there is still no evidence for its involvement in developing diet-induced obesity. Here we examine, using male C57BL6/J mice and patch-clamp electrophysiology, how chronic high-fat high-sugar (HFHS) diet changes the physiology of the VP and whether mice that gain the most weight differ in their VP physiology from others. We found that 10-12 weeks of HFHS diet hyperpolarized and decreased the firing rate of VP neurons without a major change in synaptic inhibitory input. Within the HFHS group, the top 33% weight gainers (WGs) had a more hyperpolarized VP with longer latency to fire action potentials on depolarization compared with bottom 33% of weight gainers (i.e., non-weight gainers). WGs also showed synaptic potentiation of inhibitory inputs both at the millisecond and minute ranges. Moreover, we found that the tendency to potentiate the inhibitory inputs to the VP might exist in overeating mice even before exposure to HFHS, thus making it a potential property of being an overeater. These data point to the VP as a critical player in obesity and suggest that hyperpolarized membrane potential of, and potentiated inhibitory inputs to, VP neurons may play a significant role in promoting the overeating of palatable food.SIGNIFICANCE STATEMENT In modern world, where highly palatable food is readily available, overeating is often driven by motivational, rather than metabolic, needs. It is thus conceivable that reward circuits differ between obese and normal-weight individuals. But is such difference, if it exists, innate or does it develop with overeating? Here we reveal synaptic properties in the ventral pallidum, a central hub of reward circuits, that differ between mice that gain the most and the least weight when given unlimited access to highly palatable food. We show that these synaptic differences also exist without exposure to palatable food, potentially making them innate properties that render some more susceptible than others to overeat. Thus, the propensity to overeat may have a strong innate component embedded in reward circuits.
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Wright WJ, Dong Y. Psychostimulant-Induced Adaptations in Nucleus Accumbens Glutamatergic Transmission. Cold Spring Harb Perspect Med 2020; 10:cshperspect.a039255. [PMID: 31964644 DOI: 10.1101/cshperspect.a039255] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
Carrying different aspects of emotional and motivational signals, glutamatergic synaptic projections from multiple limbic and paralimbic brain regions converge to the nucleus accumbens (NAc), in which these arousing signals are processed and prioritized for behavioral output. In animal models of drug addiction, some key drug-induced alterations at NAc glutamatergic synapses underlie important cellular and circuit mechanisms that promote subsequent drug taking, seeking, and relapse. With the focus of cocaine, we review changes at NAc glutamatergic synapses that occur after different drug procedures and abstinence durations, and the behavioral impact of these changes.
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Affiliation(s)
- William J Wright
- Department of Neuroscience, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, USA
| | - Yan Dong
- Department of Neuroscience, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, USA
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Neuhofer D, Spencer SM, Chioma VC, Beloate LN, Schwartz D, Kalivas PW. The loss of NMDAR-dependent LTD following cannabinoid self-administration is restored by positive allosteric modulation of CB1 receptors. Addict Biol 2020; 25:e12843. [PMID: 31733097 PMCID: PMC7962172 DOI: 10.1111/adb.12843] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2019] [Revised: 09/28/2019] [Accepted: 09/30/2019] [Indexed: 02/04/2023]
Abstract
Glutamatergic plasticity in the nucleus accumbens core (NAcore) is a key neuronal process in appetitive learning and contributes to pathologies such as drug addiction. Understanding how this plasticity factors into cannabis addiction and relapse has been hampered by the lack of a rodent model of cannabis self-administration. We used intravenous self-administration of two constituents of cannabis, Δ9 -tetrahydrocannabinol (THC) and cannabidiol (CBD) to examine how contingent cannabis use and cue-induced cannabinoid-seeking alters glutamatergic neurotransmission and synaptic plasticity in NAcore. NMDA receptor (NMDAR)-dependent long-term depression (LTD) in the NAcore was lost after cannabinoid, but not sucrose self-administration. Surprisingly, when rats underwent cue-induced cannabinoid seeking, LTD was restored. Loss of LTD was accompanied by desensitization of cannabinoid receptor 1 (CB1R). CB1R are positioned to regulate synaptic plasticity by being expressed on glutamatergic terminals and negatively regulating presynaptic excitability and glutamate release. Supporting this possibility, LTD was restored by promoting CB1R signaling with the CB1 positive allosteric modulator GAT211. These data implicate NAcore CB1R as critical regulators of metaplasticity induced by cannabis self-administration and the cues predicting cannabis availability.
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Affiliation(s)
- Daniela Neuhofer
- Department of Neurosciences, Medical University of South Carolina, Charleston, South Carolina
| | - Sade M. Spencer
- Department of Neurosciences, Medical University of South Carolina, Charleston, South Carolina
- Department of Pharmacology, Medical Discovery Team on Addiction, University of Minnesota, Minneapolis, Minnesota
| | - Vivian C. Chioma
- Department of Neurosciences, Medical University of South Carolina, Charleston, South Carolina
| | - Lauren N. Beloate
- Department of Neurosciences, Medical University of South Carolina, Charleston, South Carolina
| | - Danielle Schwartz
- Department of Neurosciences, Medical University of South Carolina, Charleston, South Carolina
| | - Peter W. Kalivas
- Department of Neurosciences, Medical University of South Carolina, Charleston, South Carolina
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