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Yan ZW, Liu YN, Xu Q, Yuan Y. Current trends and hotspots of depressive disorders with colorectal cancer: A bibliometric and visual study. World J Gastrointest Oncol 2024; 16:3687-3704. [PMID: 39171183 PMCID: PMC11334043 DOI: 10.4251/wjgo.v16.i8.3687] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2024] [Revised: 05/26/2024] [Accepted: 06/17/2024] [Indexed: 08/07/2024] Open
Abstract
BACKGROUND Depression is strongly associated with colorectal cancer (CRC). Few bibliometric analyses have systematically summarized the research focus and recent progress in this field. AIM To determine the research status and hotspots by bibliometric analysis of relevant publications on the relationship between CRC and depression. METHODS Articles on depression in CRC patients were collected from the Web of Science Core Collection. CiteSpace and VOSviewer software were used to visualize bibliometric networks. RESULTS From 2001 to 2022, Supportive Care in Cancer, the United States, Tilburg University, and Mols were the most productive and influential journal, country, institution, and author name. Co-occurrence cluster analysis of keywords placed quality of life, anxiety, and psychological stress in the center of the visual network diagram. Further clustering was performed for the clusters with studies of the relevant mechanism of action, which showed that: (1) Cytokines have a role essential for the occurrence and development of depressive disorders in CRC; (2) MicroRNAs have a role essential for the development of depressive disorders in CRC; (3) Some anticancer drugs have pro-depressant activity; and (4) Selective serotonin reuptake inhibitors have both antitumor and antidepressant activity. CONCLUSION Life quality and psychological nursing of the cancer population were key topics. The roles of cytokines and microRNAs, the pro-depression activity of anticancer drugs and their antitumor properties deserve in-depth study.
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Affiliation(s)
- Zi-Wei Yan
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
- Key Laboratory of Cancer Etiology and Prevention in Liaoning Education Department, The First Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
- Key Laboratory of GI Cancer Etiology and Prevention in Liaoning Province, The First Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
| | - Ying-Nan Liu
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
- Key Laboratory of Cancer Etiology and Prevention in Liaoning Education Department, The First Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
- Key Laboratory of GI Cancer Etiology and Prevention in Liaoning Province, The First Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
| | - Qian Xu
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
- Key Laboratory of Cancer Etiology and Prevention in Liaoning Education Department, The First Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
- Key Laboratory of GI Cancer Etiology and Prevention in Liaoning Province, The First Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
| | - Yuan Yuan
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
- Key Laboratory of Cancer Etiology and Prevention in Liaoning Education Department, The First Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
- Key Laboratory of GI Cancer Etiology and Prevention in Liaoning Province, The First Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
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Chen ZJ, Su CW, Xiong S, Li T, Liang HY, Lin YH, Chang L, Wu HY, Li F, Zhu DY, Luo CX. Enhanced AMPAR-dependent synaptic transmission by S-nitrosylation in the vmPFC contributes to chronic inflammatory pain-induced persistent anxiety in mice. Acta Pharmacol Sin 2023; 44:954-968. [PMID: 36460834 PMCID: PMC10104852 DOI: 10.1038/s41401-022-01024-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Accepted: 11/02/2022] [Indexed: 12/04/2022]
Abstract
Chronic pain patients often have anxiety disorders, and some of them suffer from anxiety even after analgesic administration. In this study, we investigated the role of AMPAR-mediated synaptic transmission in the ventromedial prefrontal cortex (vmPFC) in chronic pain-induced persistent anxiety in mice and explored potential drug targets. Chronic inflammatory pain was induced in mice by bilateral injection of complete Freund's adjuvant (CFA) into the planta of the hind paws; anxiety-like behaviours were assessed with behavioural tests; S-nitrosylation and AMPAR-mediated synaptic transmission were examined using biochemical assays and electrophysiological recordings, respectively. We found that CFA induced persistent upregulation of AMPAR membrane expression and function in the vmPFC of anxious mice but not in the vmPFC of non-anxious mice. The anxious mice exhibited higher S-nitrosylation of stargazin (an AMPAR-interacting protein) in the vmPFC. Inhibition of S-nitrosylation by bilaterally infusing an exogenous stargazin (C302S) mutant into the vmPFC rescued the surface expression of GluA1 and AMPAR-mediated synaptic transmission as well as the anxiety-like behaviours in CFA-injected mice, even after ibuprofen treatment. Moreover, administration of ZL006, a small molecular inhibitor disrupting the interaction of nNOS and PSD-95 (20 mg·kg-1·d-1, for 5 days, i.p.), significantly reduced nitric oxide production and S-nitrosylation of AMPAR-interacting proteins in the vmPFC, resulting in anxiolytic-like effects in anxious mice after ibuprofen treatment. We conclude that S-nitrosylation is necessary for AMPAR trafficking and function in the vmPFC under chronic inflammatory pain-induced persistent anxiety conditions, and nNOS-PSD-95 inhibitors could be potential anxiolytics specific for chronic inflammatory pain-induced persistent anxiety after analgesic treatment.
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Affiliation(s)
- Zhi-Jin Chen
- Department of Pharmacology, School of Pharmacy, Nanjing Medical University, Nanjing, 211166, China
| | - Chun-Wan Su
- Department of Pharmacology, School of Pharmacy, Nanjing Medical University, Nanjing, 211166, China
| | - Shuai Xiong
- Department of Pharmacology, School of Pharmacy, Nanjing Medical University, Nanjing, 211166, China
| | - Ting Li
- Department of Pharmacology, School of Pharmacy, Nanjing Medical University, Nanjing, 211166, China
| | - Hai-Ying Liang
- Department of Pharmacology, School of Pharmacy, Nanjing Medical University, Nanjing, 211166, China
- The First Affiliated Hospital of Fujian Medical University, Longyan, 364000, China
| | - Yu-Hui Lin
- Department of Pharmacology, School of Pharmacy, Nanjing Medical University, Nanjing, 211166, China
| | - Lei Chang
- Department of Pharmacology, School of Pharmacy, Nanjing Medical University, Nanjing, 211166, China
| | - Hai-Yin Wu
- Department of Pharmacology, School of Pharmacy, Nanjing Medical University, Nanjing, 211166, China
- Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Guangzhou, 510515, China
| | - Fei Li
- Department of Medicinal Chemistry, School of Pharmacy, Nanjing Medical University, Nanjing, 211166, China
| | - Dong-Ya Zhu
- Department of Pharmacology, School of Pharmacy, Nanjing Medical University, Nanjing, 211166, China
- Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Guangzhou, 510515, China
| | - Chun-Xia Luo
- Department of Pharmacology, School of Pharmacy, Nanjing Medical University, Nanjing, 211166, China.
- Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Guangzhou, 510515, China.
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3
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Sabihi S, Goodpaster C, Maurer S, Leuner B. GABA in the medial prefrontal cortex regulates anxiety-like behavior during the postpartum period. Behav Brain Res 2021; 398:112967. [PMID: 33075397 PMCID: PMC7722033 DOI: 10.1016/j.bbr.2020.112967] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2020] [Revised: 10/02/2020] [Accepted: 10/07/2020] [Indexed: 01/22/2023]
Abstract
The postpartum period is commonly accompanied by emotional changes, which for many new mothers includes a reduction in anxiety. Previous research in rodents has shown that the postpartum attenuation in anxiety is dependent on offspring contact and has further implicated enhanced GABAergic neurotransmission as an underlying mechanism. However, the specific brain regions where GABA acts to regulate the offspring-induced reduction in postpartum anxiety requires further investigation. Here, we test the hypothesis that offspring interactions suppress anxiety-like behavior in postpartum female rats via GABA signaling in the medial prefrontal cortex (mPFC). Our results show a postpartum reduction in anxiety-like behavior, an effect which was abolished by localized infusion of the GABAA receptor antagonist bicuculline in the mPFC. We also show that activation of GABAA receptors in the mPFC by the agonist muscimol was effective in restoring anxiolyisis in mothers separated from their pups. Lastly, we show that heightened anxiety-like behavior in pup-separated mothers was accompanied by a lower number and percentage of activated GABAergic neurons within the mPFC. Together, these results suggest that mother-offspring interactions reduce anxiety-like behavior in postpartum females via GABAA neurotransmission in the mPFC and in doing so provide insight into mechanisms that may become dysfunctional in mothers who experience high postpartum anxiety.
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Affiliation(s)
- Sara Sabihi
- Department of Psychology, The Ohio State University Columbus, OH 43210, USA
| | - Caitlin Goodpaster
- Department of Psychology, The Ohio State University Columbus, OH 43210, USA
| | - Skyler Maurer
- Department of Psychology, The Ohio State University Columbus, OH 43210, USA
| | - Benedetta Leuner
- Department of Psychology, The Ohio State University Columbus, OH 43210, USA; Department of Neuroscience, The Ohio State University Columbus, OH 43210, USA.
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4
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Green TA, Baracz SJ, Everett NA, Robinson KJ, Cornish JL. Differential effects of GABA A receptor activation in the prelimbic and orbitofrontal cortices on anxiety. Psychopharmacology (Berl) 2020; 237:3237-3247. [PMID: 32666257 DOI: 10.1007/s00213-020-05606-9] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2020] [Accepted: 07/01/2020] [Indexed: 10/23/2022]
Abstract
RATIONALE The development of effective anxiety treatments has been hindered by limited understanding of the neurobiological mechanisms involved in anxiety regulation. Whilst gamma-aminobutyric acid (GABA) neurotransmission in the prefrontal cortex (PFC) is one mechanism consistently implicated in anxiety regulation, PFC subregions may contribute uniquely. OBJECTIVES The present study examined the effects of inactivating the PFC subregions of the prelimbic cortex (PrL) or orbitofrontal cortex (OFC) through GABAA receptor (GABAAR) activation, on anxiety behaviours in male Wistar rats. METHODS Sixty-six male Wistar rats were surgically implanted with bilateral cannulae into the PrL (n = 33) or the OFC (n = 33). Rats then received a microinjection of either the GABAA receptor agonist muscimol or vehicle prior to each experiment, conducted 1 week apart. Measures of anxiety were examined using the elevated plus maze (EPM) and the emergence test (ET). The effect on locomotor activity (baseline or methamphetamine-induced) was also tested. RESULTS Differential effects of brain region inactivation on anxiety-like behaviour were shown by measures in the EPM and ET; muscimol infused into the PrL-reduced anxiety-like behaviour, yet had no significant effect when infused into the OFC, compared with control treated rats. No effects on locomotor activity at baseline or following methamphetamine treatment were found. CONCLUSIONS This study highlights that activation of GABAARs specifically within the PrL, but not OFC, reduces anxiety behaviours in male rats. This suggests that activity of the PrL plays a more important role than the OFC in the neurobiological mechanisms of unconditioned anxiety and should be targeted for future therapies.
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Affiliation(s)
- Trudy A Green
- Department of Psychology, Macquarie University, Sydney, NSW, 2109, Australia
| | - Sarah J Baracz
- Department of Psychology, Macquarie University, Sydney, NSW, 2109, Australia.,Centre for Emotional Health, Macquarie University, Sydney, NSW, 2109, Australia
| | - Nick A Everett
- Department of Psychology, Macquarie University, Sydney, NSW, 2109, Australia
| | - Katherine J Robinson
- Department of Biomedical Sciences, Macquarie University, Sydney, NSW, 2109, Australia
| | - Jennifer L Cornish
- Department of Psychology, Macquarie University, Sydney, NSW, 2109, Australia. .,Centre for Emotional Health, Macquarie University, Sydney, NSW, 2109, Australia.
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Gholaminejad A, Gholamipour-Badie H, Nasehi M, Naghdi N. Prelimbic of Medial Prefrontal Cortex GABA Modulation through Testosterone on Spatial Learning and Memory. IRANIAN JOURNAL OF PHARMACEUTICAL RESEARCH : IJPR 2020; 18:1429-1444. [PMID: 32641952 PMCID: PMC6934985 DOI: 10.22037/ijpr.2019.1100745] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
Prefrontal cortex (PFC) is involved in multiple functions including attentional processes, spatial orientation, short-term memory, and long-term memory. Our previous study indicated that microinjection of testosterone in CA1 impaired spatial learning and memory. Some evidence suggests that impairment effect of testosterone is mediated by GABAergic system. In the present study, we investigated the interaction of testosterone (androgenic receptor agonist) and bicuculline (GABAA receptor antagonist) on spatial learning and memory performance in the prelimbic (PL) of male Wistar rats. Cannulae were bilaterally implanted into the PL region of PFC and drugs were daily microinjected for two minutes in each side. There are 4 experiments. In the first experiment, three sham groups were operated (solvent of testosterone, bicuculline, testosterone plus bicuculline). In the second experiment, different doses of testosterone (40, 80 μg /0.5 μL DMSO/each side) were injected into the PL before each session. In the third experiment, intra PL injections of bicuculline (2, 4 μg/0.5 μL DMSO/each side) were given before every session. In the last experiment, testosterone (80μg/0.5 μL DMSO/each side) along with bicuculline (2 μg/0.5 μL DMSO/each side) was injected into the PL. The results showed there is no difference between control group and sham operated group. Testosterone 80 μg and bicuculline 2 μg, each given separately, and also in combination increased escape latency to find the platform compared to the sham operated and cause to impaired spatial learning and memory. It is shown that intra PL microinjection of bicuculline after testosterone treatment could not rescue the spatial learning and memory impaired induced by testosterone.
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Affiliation(s)
- Azadeh Gholaminejad
- Department of Physiology and Pharmacology, Pasteur Institute of Iran (IPI), Tehran, Iran.,Department of Cognitive Neuroscience, Institute for Cognitive Science Studies (ICSS), Tehran, Iran
| | | | - Mohammad Nasehi
- Department of Cognitive Neuroscience, Institute for Cognitive Science Studies (ICSS), Tehran, Iran.,Cognitive and neuroscience research center (CNRC), Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Nasser Naghdi
- Department of Physiology and Pharmacology, Pasteur Institute of Iran (IPI), Tehran, Iran.,Department of Cognitive Neuroscience, Institute for Cognitive Science Studies (ICSS), Tehran, Iran
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Zhang F, Chen H, Zhang R, Liu Y, Kong N, Guo Y, Xu M. 5-Fluorouracil induced dysregulation of the microbiome-gut-brain axis manifesting as depressive like behaviors in rats. Biochim Biophys Acta Mol Basis Dis 2020; 1866:165884. [PMID: 32574836 DOI: 10.1016/j.bbadis.2020.165884] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2020] [Revised: 04/08/2020] [Accepted: 06/17/2020] [Indexed: 02/08/2023]
Abstract
Disturbances of the gut microbiome have been widely suggested to be associated with 5-fluorouracil (5-Fu) induced digestive pathologies. Furthermore, it has been elucidated that the gut microbiome may play a key role in the pathogenesis of depressive disorders via the microbiota-gut-brain axis. Despite the speculation, there exists no direct evidence proving the causality between disturbances in the gut microbiome induced by 5-Fu and depressive mood dysregulation. Herein, behavioral testing was used to evaluate depressive-like behaviors in 5-Fu treated rats. Subsequently, the gut microbiota and prefrontal cortex (PFC) metabolic were analyzed by 16S rRNA sequencing and 1H nuclear magnetic resonance (1H NMR). To clarify the association between the gut microbiota and their role on depressive-like behaviors caused by 5-Fu, a fecal microbiota transplantation (FMT) experiment was carried out. The results suggested that 5-Fu could significantly alter the diversity and abundance of the gut microbiome, and induce PFC metabolic disorders, as well as depressive behaviors in rats. Transplantation of fecal microbiota from healthy control into 5-Fu treated rats significantly alleviated the PFC metabolic disorder and depressive-like behaviors. In conclusion, this study demonstrated that the gut microbiome was actively involved in the occurrence of 5-Fu induced depressive-like behaviors, and manipulation of specific gut microbiome parameters may serve as a promising novel target for side effects of 5-Fu treatment.
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Affiliation(s)
- Fan Zhang
- The First Clinical College of Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, China; Department of Radiology, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310003, China
| | - Haitao Chen
- The First Clinical College of Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, China
| | - Ruixin Zhang
- Department of Radiology, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310003, China
| | - Yu Liu
- College of Life Sciences, Zhejiang University, Hangzhou, Zhejiang 310000, China
| | - Ning Kong
- The First Clinical College of Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, China
| | - Yong Guo
- Department of Oncology, First Affiliated Hospital of Zhejiang Traditional Medical University, Hangzhou, Zhejiang 310003, China.
| | - Maosheng Xu
- Department of Radiology, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310003, China.
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nNOS-expressing neurons in the vmPFC transform pPVT-derived chronic pain signals into anxiety behaviors. Nat Commun 2020; 11:2501. [PMID: 32427844 PMCID: PMC7237711 DOI: 10.1038/s41467-020-16198-5] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2019] [Accepted: 04/21/2020] [Indexed: 01/30/2023] Open
Abstract
Anxiety is common in patients suffering from chronic pain. Here, we report anxiety-like behaviors in mouse models of chronic pain and reveal that nNOS-expressing neurons in ventromedial prefrontal cortex (vmPFC) are essential for pain-induced anxiety but not algesia, using optogenetic and chemogenetic strategies. Additionally, we determined that excitatory projections from the posterior subregion of paraventricular thalamic nucleus (pPVT) provide a neuronal input that drives the activation of vmPFC nNOS-expressing neurons in our chronic pain models. Our results suggest that the pain signal becomes an anxiety signal after activation of vmPFC nNOS-expressing neurons, which causes subsequent release of nitric oxide (NO). Finally, we show that the downstream molecular mechanisms of NO likely involve enhanced glutamate transmission in vmPFC CaMKIIα-expressing neurons through S-nitrosylation-induced AMPAR trafficking. Overall, our data suggest that pPVT excitatory neurons drive chronic pain-induced anxiety through activation of vmPFC nNOS-expressing neurons, resulting in NO-mediated AMPAR trafficking in vmPFC pyramidal neurons. Chronic pain usually induces anxiety. Here, the authors report that vmPFC nNOS-expressing neurons are activated by excitatory inputs from pPVT during chronic pain and subsequently induce anxiety-like behaviors in mice through promoting AMPAR trafficking.
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8
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Rapid Anxiolytic Effects of RS67333, a Serotonin Type 4 Receptor Agonist, and Diazepam, a Benzodiazepine, Are Mediated by Projections From the Prefrontal Cortex to the Dorsal Raphe Nucleus. Biol Psychiatry 2020; 87:514-525. [PMID: 31623825 DOI: 10.1016/j.biopsych.2019.08.009] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2019] [Revised: 08/02/2019] [Accepted: 08/08/2019] [Indexed: 11/20/2022]
Abstract
BACKGROUND Activation of serotonin (5-HT) type 4 receptors (5-HT4Rs) has been shown to have anxiolytic effects in a variety of animal models. Characterizing the circuits responsible for these effects should offer insights into new approaches to treat anxiety. METHODS We evaluated whether acute 5-HT4R activation in glutamatergic axon terminals arising from the medial prefrontal cortex (mPFC) to the dorsal raphe nucleus (DRN) induced fast anxiolytic effects. Anxiolytic effects of an acute systemic administration (1.5 mg/kg, intraperitoneally) or intra-mPFC infusion with the 5-HT4R agonist, RS67333 (0.5 μg/side), were examined in mice. To provide evidence that anxiolytic effects of RS67333 recruited an mPFC-DRN neural circuit, in vivo recordings of firing rate of DRN 5-HT neurons, cerebral 5-HT depletion, and optogenetic activation and silencing were performed. RESULTS Acute systemic administration and intra-mPFC infusion of RS67333 produced fast anxiolytic effects and increased DRN 5-HT cell firing. Serotonin depletion prevented anxiolytic effects induced by mPFC infusion of RS67333. Surprisingly the anxiolytic effects of mPFC infusion diazepam (1.5 μg/side) were also blocked by 5-HT depletion. Optogenetically activating mPFC terminals targeting the DRN reduced anxiety, whereas silencing this circuit blocked RS67333 and diazepam mPFC infusion-induced anxiolytic effects. Finally, anxiolytic effects induced by an acute systemic RS67333 or diazepam administration were partially blocked after optogenetically inhibiting cortical glutamatergic terminals in the DRN. CONCLUSIONS Our findings suggest that activating 5-HT4R acutely in the mPFC or targeting mPFC pyramidal cell terminals in the DRN might constitute a strategy to produce a fast anxiolytic response.
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9
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Norepinephrine, neurodevelopment and behavior. Neurochem Int 2020; 135:104706. [PMID: 32092327 DOI: 10.1016/j.neuint.2020.104706] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2020] [Revised: 02/14/2020] [Accepted: 02/16/2020] [Indexed: 02/06/2023]
Abstract
Neurotransmitters play critical roles in the developing nervous system. Among the neurotransmitters, norepinephrine (NE) is in particular postulated to be an important regulator of brain development. NE is expressed during early stages of development and is known to regulate both the development of noradrenergic neurons and the development of target areas. NE participates in the shaping and the wiring of the nervous system during the critical periods of development, and perturbations in this process can alter the brain's developmental trajectory, which in turn can cause long-lasting and even permanent changes in the brain function and behavior later in life. Here we will briefly review evidence for the role of noradrenergic system in neurodevelopmental processes and will discuss about the potential disruptors of noradrenergic system during development and their behavioral consequences.
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10
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Pham TH, Gardier AM. Fast-acting antidepressant activity of ketamine: highlights on brain serotonin, glutamate, and GABA neurotransmission in preclinical studies. Pharmacol Ther 2019; 199:58-90. [DOI: 10.1016/j.pharmthera.2019.02.017] [Citation(s) in RCA: 73] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2018] [Accepted: 02/25/2019] [Indexed: 12/13/2022]
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11
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Dorsomedial prefrontal cortex 5-HT6 receptors regulate anxiety-like behavior. COGNITIVE AFFECTIVE & BEHAVIORAL NEUROSCIENCE 2019; 18:58-67. [PMID: 29204799 DOI: 10.3758/s13415-017-0552-6] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
The dorsomedial prefrontal cortex (dmPFC) plays a very important role in decision-related and anxiety-related information processing. It has enriched 5-HT6 receptors; however, the precise role of dmPFC 5-HT6 receptors in anxiety remains to be fully investigated. In this study, we injected dmPFC with the 5-HT6 receptor agonist EMD 386088 and antagonist SB 271046 using stereotactic technology. 5-HT6 receptor activation in mice increased time spent in the center area on the open-field test, increased exploration of the open arms on the elevated plus maze test, and increased ratio on the social interaction test. 5-HT6 receptor inactivation induced the opposite effects. In brain slices, EMD 386088 decreased both spontaneous inhibitory postsynaptic currents (sIPSC) and spontaneous excitatory postsynaptic currents (sEPSC), while SB 271046 only increased sEPSC. These effects of EMD 386088 and SB 271046 could be reversed by the GABAA receptor antagonist bicuculline (BMI) and positive allosteric modulator clonazepam (CLZ), respectively. Our results suggest that neurotransmission in the dmPFC by 5-HT6 receptor activation and inhibition may play an important role in anxiety-like behavior, and may provide new insight into the pathological mechanism and potential target of anxiety disorders.
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12
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He Y, Ouyang J, Hu Z, Yang J, Chu Y, Huang S, Yang Y, Liu C. Intervention mechanism of repeated oral GABA administration on anxiety-like behaviors induced by emotional stress in rats. Psychiatry Res 2019; 271:649-657. [PMID: 30791338 DOI: 10.1016/j.psychres.2018.12.025] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2018] [Revised: 12/03/2018] [Accepted: 12/05/2018] [Indexed: 02/07/2023]
Abstract
The purpose of this study was to investigate the effects and mechanism of repeated oral administration of gamma-aminobutyric acid (GABA) on anxiety-like behaviors induced by emotional stress. Male Sprague-Dawley rats were randomly divided into five groups (8 rats each): control, emotional stress model, three emotional stress + GABA-treated groups (0.5, 1, 2 mg/kg). The rats were given empty water bottles after the training of drinking water to induce emotional stress. Each group was treated with saline or different doses of GABA respectively for 21 consecutive days. Then open field and elevated plus maze were used to assess anxiety-like behaviors. Both frontal cortex and plasma NO metabolites nitrate and nitrite (NOx) levels were determined spectrophotometrically. Results showed that oral administration of GABA significantly reversed the stress-induced anxiety-like negative responses dose-dependently. The frontal cortex NOx levels were lower in stressed rats than in control group (P < 0.05), but higher in 2 mg/kg GABA-treated group than stress model group (P < 0.05). On the other hand, NOx levels in plasma showed a gradual decline trend. Collectively, these results suggest that short repeated oral administration of GABA has an anxiolytic-like effect possibly via preventing NO reduction caused by stress and improving availability of NO in the frontal cortex.
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Affiliation(s)
- Yongjian He
- College of Food Science, South China Agricultural University, Guangzhou, GZ, China; Guangdong Provincial Key Laboratory of Food Quality and Safety, South China Agricultural University, Guangzhou 510642, China
| | - Junyan Ouyang
- College of Food Science, South China Agricultural University, Guangzhou, GZ, China; Guangdong Provincial Key Laboratory of Food Quality and Safety, South China Agricultural University, Guangzhou 510642, China
| | - Zhuoyan Hu
- College of Food Science, South China Agricultural University, Guangzhou, GZ, China
| | - Jie Yang
- College of Food Science, South China Agricultural University, Guangzhou, GZ, China; Guangdong Provincial Key Laboratory of Food Quality and Safety, South China Agricultural University, Guangzhou 510642, China
| | - Yue Chu
- College of Food Science, South China Agricultural University, Guangzhou, GZ, China; Guangdong Provincial Key Laboratory of Food Quality and Safety, South China Agricultural University, Guangzhou 510642, China
| | - Shaowen Huang
- College of Food Science, South China Agricultural University, Guangzhou, GZ, China; Guangdong Provincial Key Laboratory of Food Quality and Safety, South China Agricultural University, Guangzhou 510642, China
| | - Yichao Yang
- School of Public Health, Guangzhou Medical University, Guangzhou, GZ, China
| | - Chunhong Liu
- College of Food Science, South China Agricultural University, Guangzhou, GZ, China; Guangdong Provincial Key Laboratory of Food Quality and Safety, South China Agricultural University, Guangzhou 510642, China.
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13
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Yaoita F, Tsuchiya M, Arai Y, Tadano T, Tan-No K. Involvement of catecholaminergic and GABAAergic mediations in the anxiety-related behavior in long-term powdered diet-fed mice. Neurochem Int 2018; 124:1-9. [PMID: 30529642 DOI: 10.1016/j.neuint.2018.12.002] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2018] [Revised: 11/30/2018] [Accepted: 12/04/2018] [Indexed: 11/26/2022]
Abstract
Dietary habits are important factors which affect metabolic homeostasis and the development of emotion. We have previously shown that long-term powdered diet feeding in mice increases spontaneous locomotor activity and social interaction (SI) time. Moreover, that diet causes changes in the dopaminergic system, especially increased dopamine turnover and decreased dopamine D4 receptor signals in the frontal cortex. Although the increased SI time indicates low anxiety, the elevated plus maze (EPM) test shows anxiety-related behavior and impulsive behavior. In this study, we investigated whether the powdered diet feeding causes changes in anxiety-related behavior. Mice fed a powdered diet for 17 weeks from weaning were compared with mice fed a standard diet (control). The percentage (%) of open arm time and total number of arm entries were increased in powdered diet-fed mice in the EPM test. We also examined the effects of diazepam, benzodiazepine anti-anxiety drug, bicuculline, GABA-A receptor antagonist, methylphenidate, dopamine transporter (DAT) and noradrenaline transporter (NAT) inhibitor, atomoxetine, selective NAT inhibitor, GBR12909, selective DAT inhibitor, and PD168077, selective dopamine D4 receptor agonist, on the changes of the EPM in powdered diet-fed mice. Methylphenidate and atomoxetine are clinically used to treat attention deficit/hyperactivity disorder (ADHD) symptoms. The % of open arm time in powdered diet-fed mice was decreased by treatments of atomoxetine, methylphenidate and PD168077. Diazepam increased the % of open arm time in control diet-fed mice, but not in powdered diet-fed mice. The powdered diet feeding induced a decrease in GABA transaminase, GABA metabolic enzymes, in the frontal cortex. Moreover, the powdered diet feeding induced an increase in NAT expression, but not DAT expression, in the frontal cortex. These results suggest that the long-term powdered diet feeding may cause low anxiety or impulsivity, possibly via noradrenergic and/or dopaminergic, and GABAAergic mediations and increase the risk for onset of ADHD-like behaviors.
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Affiliation(s)
- Fukie Yaoita
- Department of Pharmacology, Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai, 981-8558, Japan.
| | - Masahiro Tsuchiya
- Department of Nursing, Tohoku Fukushi University, 1-8-1 Kunimi, Aoba-ku, Sendai, 981-8522, Japan
| | - Yuichiro Arai
- Tokyo Ariake University of Medical and Health Science, 2-9-1 Ariake, Koto-Ku, Tokyo, 135-0063, Japan
| | - Takeshi Tadano
- Complementary and Alternative Medicine Clinical Research and Development, Graduate School of Medicine Sciences, Kanazawa University, Kakumamachi, Kanazawa, 920-1192, Japan
| | - Koichi Tan-No
- Department of Pharmacology, Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai, 981-8558, Japan
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14
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Carbone S, Ponzo OJ, Gobetto N, Samaniego YA, Reynoso R, Moguilevsky JA, Cutrera RA. Effect of di(2-ethylhexyl) phthalate on the neuroendocrine regulation of reproduction in adult male rats and its relationship to anxiogenic behavior: Participation of GABAergic system. Hum Exp Toxicol 2018; 38:25-35. [DOI: 10.1177/0960327118774868] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
The endocrine disruptor di-(2-ethylhexyl) phthalate (DEHP) is used in a variety of consumer products made with polyvinyl chloride and also in the manufacture of medical devices. DEHP disrupts reproductive tract development in an antiandrogenic manner and also may induce neurobehavioral changes. The aim of this study was to investigate the effects of chronic postnatal exposure to DEHP (30 mg/kg body weight/day, orally from birth to day 60) on the neuroendocrine regulation of the gonadal axis and its impact on the anxiety-like behavior in adult male rats, as well as the probable participation of the GABAergic system in these effects. DEHP produced a significant increase in plasmatic luteinizing hormone and follicle stimulating hormone, as well as significant testosterone decrease, accompanied with a decrease in hypothalamic gamma-aminobutyric acid (GABA) concentration. On the other hand, DEHP increased the anxiety-like behavior in the elevated plus maze test, evidenced by a significant decrease in the percentages of time spent in the open arms and the frequency in the open arm entries and a significant increase in the percentage of time spent in closed arms. Neuroendocrine and behavioral effects were reversed by GABA agonists, muscimol (2 mg/kg i.p. ) and baclofen (10 mg/kg i.p.). In conclusion, chronic DEHP postnatal exposure induced a disruption in the neuroendocrine regulation of the testicular axis in young adult male rats, and this effect was correlated with an anxiety-like behavior. Since GABA agonists reversed these effects, the results suggest that GABA could participate in the modulation of reproductive and behavioral DEHP effects.
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Affiliation(s)
- S Carbone
- Laboratorio de Endocrinologí, Departamento de Fisiologí, Facultad de Medicina, Universidad de Buenos Aires. Buenos Aires, Argentina
- Laboratorio de Neurobiologí y Ritmos, Instituto de Fisiologí y Biofísica Bernardo Houssay (IFIBIO), Universidad de Buenos Aires and CONICET, Buenos Aires, Argentina
| | - OJ Ponzo
- Laboratorio de Endocrinologí, Departamento de Fisiologí, Facultad de Medicina, Universidad de Buenos Aires. Buenos Aires, Argentina
| | - N Gobetto
- Laboratorio de Endocrinologí, Departamento de Fisiologí, Facultad de Medicina, Universidad de Buenos Aires. Buenos Aires, Argentina
| | - YA Samaniego
- Laboratorio de Endocrinologí, Departamento de Fisiologí, Facultad de Medicina, Universidad de Buenos Aires. Buenos Aires, Argentina
| | - R Reynoso
- Laboratorio de Endocrinologí, Departamento de Fisiologí, Facultad de Medicina, Universidad de Buenos Aires. Buenos Aires, Argentina
| | - JA Moguilevsky
- Facultad de Ciencias Médicas, Universidad Favaloro. Buenos Aires, Argentina
| | - RA Cutrera
- Laboratorio de Neurobiologí y Ritmos, Instituto de Fisiologí y Biofísica Bernardo Houssay (IFIBIO), Universidad de Buenos Aires and CONICET, Buenos Aires, Argentina
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15
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Sabihi S, Dong SM, Maurer SD, Post C, Leuner B. Oxytocin in the medial prefrontal cortex attenuates anxiety: Anatomical and receptor specificity and mechanism of action. Neuropharmacology 2017; 125:1-12. [PMID: 28655609 DOI: 10.1016/j.neuropharm.2017.06.024] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2017] [Revised: 06/21/2017] [Accepted: 06/23/2017] [Indexed: 01/12/2023]
Abstract
Numerous studies in animals and humans have established that oxytocin (OT) reduces anxiety. In rats, the prelimbic (PL) subregion of the medial prefrontal cortex (mPFC) is among the brain areas implicated in the anxiolytic actions of OT. However, questions remain about the anatomical and receptor specificity of OT and its mechanism of action. Here we assessed whether the regulation of anxiety by mPFC OT is restricted to the PL subregion and evaluated whether oxytocin receptor (OTR) activation is required for OT to have an anxiolytic effect. We also examined whether OT interacts with GABA in the mPFC to reduce anxiety and investigated the extent to which OT in the mPFC affects activation of mPFC GABA neurons as well as neuronal activation in the amygdala, a primary target of the mPFC which is part of the neural network regulating anxiety. We found that OT reduced anxiety-like behavior when delivered to the PL, but not infralimbic or anterior cingulate subregions of the mPFC. The anxiolytic effect of OT in the PL mPFC was blocked by pretreatment with an OTR, but not a vasopressin receptor, antagonist as well as with a GABAA receptor antagonist. Lastly, administration of OT to the PL mPFC was accompanied by increased activation of GABA neurons in the PL mPFC and altered neuronal activation of the amygdala following anxiety testing. These results demonstrate that OT in the PL mPFC attenuates anxiety-related behavior and may do so by engaging GABAergic neurons which ultimately modulate downstream brain regions implicated in anxiety.
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Affiliation(s)
- Sara Sabihi
- The Ohio State University, Department of Psychology, Columbus, OH 43210, United States
| | - Shirley M Dong
- The Ohio State University, Department of Psychology, Columbus, OH 43210, United States
| | - Skyler D Maurer
- The Ohio State University, Department of Psychology, Columbus, OH 43210, United States
| | - Caitlin Post
- The Ohio State University, Department of Psychology, Columbus, OH 43210, United States
| | - Benedetta Leuner
- The Ohio State University, Department of Psychology, Columbus, OH 43210, United States; The Ohio State University, Department of Neuroscience, Columbus, OH 43210, United States; The Ohio State University, Behavioral Neuroendocrinology Group, Columbus, OH 43210, United States.
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Kuniishi H, Ichisaka S, Matsuda S, Futora E, Harada R, Hata Y. Chronic Inactivation of the Orbitofrontal Cortex Increases Anxiety-Like Behavior and Impulsive Aggression, but Decreases Depression-Like Behavior in Rats. Front Behav Neurosci 2017; 10:250. [PMID: 28167902 PMCID: PMC5253363 DOI: 10.3389/fnbeh.2016.00250] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2016] [Accepted: 12/22/2016] [Indexed: 11/13/2022] Open
Abstract
The orbitofrontal cortex (OFC) is involved in emotional processing, and orbitofrontal abnormalities have often been observed in various affective disorders. Thus, chronic dysfunction of the OFC may cause symptoms of affective disorders, such as anxiety, depression and impulsivity. Previous studies have investigated the effect of orbitofrontal dysfunction on anxiety-like behavior and impulsive aggression in rodents, but the results are inconsistent possibly reflecting different methods of OFC inactivation. These studies used either a lesion of the OFC, which may affect other brain regions, or a transient inactivation of the OFC, whose effect may be restored in time and not reflect effects of chronic OFC dysfunction. In addition, there has been no study on the effect of orbitofrontal inactivation on depression-like behavior in rodents. Therefore, the present study examined whether chronic inactivation of the OFC by continuous infusion of a GABAA receptor agonist, muscimol, causes behavioral abnormalities in rats. Muscimol infusion inactivated the ventral and lateral part of the OFC. Following a week of OFC inactivation, the animals showed an increase in anxiety-like behavior in the open field test and light-dark test. Impulsive aggression was also augmented in the chronically OFC-inactivated animals because they showed increased frequency of fighting behavior induced by electric foot shock. On the other hand, chronic OFC inactivation reduced depression-like behavior as evaluated by the forced swim test. Additionally, it did not cause a significant change in corticosterone secretion in response to restraint stress. These data suggest that orbitofrontal neural activity is involved in the regulation of anxiety- and depression-like behaviors and impulsive aggression in rodents.
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Affiliation(s)
- Hiroshi Kuniishi
- Division of Integrative Bioscience, Institute of Regenerative Medicine and Biofunction, Tottori University Graduate School of Medical Sciences Yonago, Japan
| | - Satoshi Ichisaka
- Division of Neurobiology, School of Life Sciences, Faculty of Medicine, Tottori University Yonago, Japan
| | - Sae Matsuda
- Division of Integrative Bioscience, Institute of Regenerative Medicine and Biofunction, Tottori University Graduate School of Medical Sciences Yonago, Japan
| | - Eri Futora
- Division of Neurobiology, School of Life Sciences, Faculty of Medicine, Tottori University Yonago, Japan
| | - Riho Harada
- Division of Neurobiology, School of Life Sciences, Faculty of Medicine, Tottori University Yonago, Japan
| | - Yoshio Hata
- Division of Integrative Bioscience, Institute of Regenerative Medicine and Biofunction, Tottori University Graduate School of Medical Sciences Yonago, Japan
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17
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Paine TA, Swedlow N, Swetschinski L. Decreasing GABA function within the medial prefrontal cortex or basolateral amygdala decreases sociability. Behav Brain Res 2016; 317:542-552. [PMID: 27732892 DOI: 10.1016/j.bbr.2016.10.012] [Citation(s) in RCA: 64] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2016] [Revised: 09/28/2016] [Accepted: 10/07/2016] [Indexed: 01/29/2023]
Abstract
INTRODUCTION Decreased sociability is a symptom of psychiatric conditions including autism-spectrum disorder and schizophrenia. Both of these conditions are associated with decreases in GABA function, particularly in the medial prefrontal cortex (PFC) and the basolateral amygdala (BLA); structures that are components of the social brain. Here, we determined if decreasing GABA transmission within either the PFC or the BLA decreases social behavior. METHODS Rats were implanted with cannulae aimed at either the medial PFC or the BLA and then were tested on up to 4 behavioral tests following bilateral infusions of 0.5μl bicuculline methiodide (BMI, a GABAA receptor antagonist) at doses of 0, 25, or 50ng/μl. Rats were tested in the social interaction test, the social preference test, the sucrose preference test and for locomotor activity (BLA infusions only). RESULTS Intra-BLA or PFC BMI infusions decreased the amount of time and the number of social interactions in the social interaction test. Further, in the social preference test, rats infused with 50ng BMI no longer exhibited a preference to explore a social over a non-social stimulus. The change in sociability was not due to a change in reward processing or locomotor behavior. DISCUSSION Decreasing GABA transmission in either the medial PFC or BLA decreased sociability. Thus, changes in GABA signaling observed in conditions such as autism or schizophrenia may mediate the social withdrawal characteristic of these conditions. Moreover, they suggest that social withdrawal may be treated by drugs that potentiate GABA transmission.
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Affiliation(s)
- Tracie A Paine
- Department of Neuroscience, Oberlin College, Oberlin, OH, 44074, United States.
| | - Nathan Swedlow
- Department of Neuroscience, Oberlin College, Oberlin, OH, 44074, United States
| | - Lucien Swetschinski
- Department of Neuroscience, Oberlin College, Oberlin, OH, 44074, United States
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Kang S, Wu MM, Galvez R, Gulley JM. Timing of amphetamine exposure in relation to puberty onset determines its effects on anhedonia, exploratory behavior, and dopamine D 1 receptor expression in young adulthood. Neuroscience 2016; 339:72-84. [PMID: 27702645 DOI: 10.1016/j.neuroscience.2016.09.044] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2016] [Revised: 09/22/2016] [Accepted: 09/26/2016] [Indexed: 10/20/2022]
Abstract
Non-medical use of amphetamine (AMPH) among adolescents is prevalent, which is problematic given the potential consequences of developmental drug exposure on brain function and behavior. Previously we found in adult male rats that AMPH exposure starting before puberty induces a persistent decrease in dopamine D1 receptor (D1R) function in the medial prefrontal cortex (mPFC). Here we investigated if this dysfunction was associated with changes in D1R expression in the mPFC and nucleus accumbens (NAc). We also determined if starting drug exposure well before or near the onset of puberty would influence AMPH-induced changes in D1R expression and behavior. Male and female Sprague-Dawley rats were treated once every other day (10 injections total) with saline or 3mg/kg AMPH (i.p.) from either postnatal day (P) 27 to 45 (pre-puberty groups; Pre-P) or P37 to 55 (peri-puberty groups; Peri-P). After 1, 7 and 21days of withdrawal, sucrose preference tests were performed to assess anhedonia. Exploratory behavior was studied in an open-field arena and on an elevated plus maze (EPM). Rats were then sacrificed for Western blot analysis of D1R expression. We found that AMPH withdrawal induced decreases in sucrose preference that persisted in rats with Peri-P onset treatment. Pre-P onset AMPH exposure led to increased open-arm exploration in the EPM test, as well as a decreased D1R level in the mPFC but not NAc. Our results demonstrated that AMPH exposure starting at different developmental stages resulted in distinct neurobehavioral abnormalities, suggesting an important role of exposure timing in drug-induced plasticity.
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Affiliation(s)
- Shuo Kang
- Neuroscience Program, University of Illinois at Urbana-Champaign, IL, USA; Beckman Institute for Advanced Science, University of Illinois at Urbana-Champaign, IL, USA
| | - Mariah M Wu
- Department of Psychology, University of Illinois at Urbana-Champaign, IL, USA
| | - Roberto Galvez
- Department of Psychology, University of Illinois at Urbana-Champaign, IL, USA; Neuroscience Program, University of Illinois at Urbana-Champaign, IL, USA; Beckman Institute for Advanced Science, University of Illinois at Urbana-Champaign, IL, USA
| | - Joshua M Gulley
- Department of Psychology, University of Illinois at Urbana-Champaign, IL, USA; Neuroscience Program, University of Illinois at Urbana-Champaign, IL, USA; Beckman Institute for Advanced Science, University of Illinois at Urbana-Champaign, IL, USA.
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