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van Koppen S, Minnaard AM, Smeets JAS, Buzatouiu I, Ramakers GMJ, Adan RAH, Vanderschuren LJMJ, Lesscher HMB. Seeking under threat of adversity: assessing control over reward pursuit in rats. Psychopharmacology (Berl) 2025; 242:803-816. [PMID: 39653798 DOI: 10.1007/s00213-024-06729-z] [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: 05/21/2024] [Accepted: 11/26/2024] [Indexed: 03/09/2025]
Abstract
RATIONALE Substance use disorder (SUD) is a chronic relapsing brain disorder that is characterised by loss of control over substance use. A variety of rodent models employing punishment setups have been developed to assess loss of control over substance use, i.e. persistent substance use despite negative consequences, to facilitate the translation of findings from animal studies to the human situation. OBJECTIVES Since the negative consequences of addictive behaviour are typically unpredictable, we here present the Seeking under Threat of Adversity (STA) task in rats, that incorporates cued, probabilistic and response-contingent punishment of reward seeking. METHODS Male rats were trained to lever press for sucrose, alcohol or cocaine and were subsequently tested in the STA task. In this task, a tone cue is presented during reward seeking which functions as a warning signal, since responding during tone presentation results in a probabilistic foot shock punishment. We first determined the optimal shock intensity to induce a moderate suppression of seeking. Next, we assessed the stability of punished reward seeking over repeated tests. Finally, we compared the development of loss of control over substance seeking for sucrose, alcohol and cocaine. (Loss of) control over substance seeking would be evident as the (in)ability to refrain from lever pressing to obtain a reward, despite the threat of a negative outcome. RESULTS Parametric experiments revealed suppression of responding for both sucrose and alcohol in the STA task at shock intensities between 0.25 and 0.35 mA. The suppression of responding was stable with repeated testing. Furthermore, less control over alcohol and cocaine seeking, when compared to sucrose seeking, was observed in male rats using the STA task. CONCLUSIONS The STA task is a novel behavioural task that includes two important aspects of human substance use despite negative consequences, i.e. response contingency and unpredictability of adversity. Combined with other behavioural tasks and neural manipulations, the STA task can further our understanding of the psychopathology of substance use disorders.
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Affiliation(s)
- Sofie van Koppen
- Department of Population Health Sciences, Unit of Animals in Science and Society, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands
- Neuroscience of Addiction (NofA) Lab, Department of Psychology, Education & Child Studies, Erasmus University Rotterdam, Rotterdam, The Netherlands
| | - A Maryse Minnaard
- Department of Population Health Sciences, Unit of Animals in Science and Society, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands
- Department of Translational Neuroscience, Brain Center, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Johanna A S Smeets
- Department of Population Health Sciences, Unit of Animals in Science and Society, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands
- Department of Translational Neuroscience, Brain Center, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Iulia Buzatouiu
- Department of Population Health Sciences, Unit of Animals in Science and Society, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands
| | - Geert M J Ramakers
- Department of Translational Neuroscience, Brain Center, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Roger A H Adan
- Department of Translational Neuroscience, Brain Center, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Louk J M J Vanderschuren
- Department of Population Health Sciences, Unit of Animals in Science and Society, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands
| | - Heidi M B Lesscher
- Department of Population Health Sciences, Unit of Animals in Science and Society, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands.
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2
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Wiegers C, Veerman MA, Brummer RJ, Larsen OFA. Reviewing the state of the art of probiotics as clinical modalities for brain-gut-microbiota axis associated disorders. Front Microbiol 2022; 13:1053958. [PMID: 36504794 PMCID: PMC9732675 DOI: 10.3389/fmicb.2022.1053958] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2022] [Accepted: 11/08/2022] [Indexed: 11/27/2022] Open
Abstract
The rise in prevalence of mental and neurological disorders is causing a high burden on society, however adequate interventions are not always available. The brain-gut-microbiota axis (BGMA) may provide a new angle for the development of clinical modalities. Due to the intricate bi-directional signaling between the brain and the gut, it may be helpful to look into interventions that target the gut, such as probiotics. Therefore, this review aimed to investigate the state of the art of probiotics and their potential as clinical modalities for BGMA-associated indications by gaining insight into patents and clinical trials that have been applied for and executed since 1999. A total of 565 patents and 390 clinical trials were found, focusing on probiotic applications for 83 indications. Since the start of the 21st century, the highest numbers of patents and clinical trials were related to primary neuropsychological, affective (depression, anxiety) and cognitive disorders, neurodegenerative and/or inflammatory brain disorders (Alzheimer's disease, Parkinson's disease, amongst others), and gastrointestinal disorders (irritable bowel syndrome). The locations where the most patents and clinical trials were registered included China, the United States, and Iran. From 1999 to ~2013 a slight growth could be seen in the numbers of patents and clinical trials, followed by an almost exponential growth from ~2013 onwards. Overall, the developments of the state of the art were in accordance with previous research, however it appeared that clinical trials showed a slightly slower growth compared to patents, which may have implications for the future implementation of probiotics as clinical modalities for BGMA-associated indications.
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Affiliation(s)
- Cato Wiegers
- Athena Institute, Vrije Universiteit Amsterdam, Amsterdam, Netherlands,*Correspondence: Cato Wiegers,
| | - Mariët A. Veerman
- Athena Institute, Vrije Universiteit Amsterdam, Amsterdam, Netherlands
| | - Robert Jan Brummer
- Faculty of Medical and Health Sciences, Nutrition-Gut-Brain Interactions Research Centre, School of Medical Sciences, Örebro University, Örebro, Sweden
| | - Olaf F. A. Larsen
- Athena Institute, Vrije Universiteit Amsterdam, Amsterdam, Netherlands
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Liu J, Liu Z, Wei Y, Zhang Y, Womer FY, Jia D, Wei S, Wu F, Kong L, Jiang X, Zhang L, Tang Y, Zhang X, Wang F. Combinatorial panel with endophenotypes from multilevel information of diffusion tensor imaging and lipid profile as predictors for depression. Aust N Z J Psychiatry 2022; 56:1187-1198. [PMID: 35632993 DOI: 10.1177/00048674211031477] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
OBJECTIVE Clinical heterogeneity in major depressive disorder likely reflects the range of etiology and contributing factors in the disorder, such as genetic risk. Identification of more refined subgroups based on biomarkers such as white matter integrity and lipid-related metabolites could facilitate precision medicine in major depressive disorder. METHODS A total of 148 participants (15 genetic high-risk participants, 57 patients with first-episode major depressive disorder and 76 healthy controls) underwent diffusion tensor imaging and plasma lipid profiling. Alterations in white matter integrity and lipid metabolites were identified in genetic high-risk participants and patients with first-episode major depressive disorder. Then, shared alterations between genetic high-risk and first-episode major depressive disorder were used to develop an imaging x metabolite diagnostic panel for genetically based major depressive disorder via factor analysis and logistic regression. A fivefold cross-validation test was performed to evaluate the diagnostic panel. RESULTS Alterations of white matter integrity in corona radiata, superior longitudinal fasciculus and the body of corpus callosum and dysregulated unsaturated fatty acid metabolism were identified in both genetic high-risk participants and patients with first-episode major depressive disorder. An imaging x metabolite diagnostic panel, consisting of measures for white matter integrity and unsaturated fatty acid metabolism, was identified that achieved an area under the receiver operating characteristic curve of 0.86 and had a significantly higher diagnostic performance than that using either measure alone. And cross-validation confirmed the adequate reliability and accuracy of the diagnostic panel. CONCLUSION Combining white matter integrity in corpus callosum, superior longitudinal fasciculus and corona radiata, and unsaturated fatty acid profile may improve the identification of genetically based endophenotypes in major depressive disorder to advance precision medicine strategies.
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Affiliation(s)
- Juan Liu
- Department of Psychiatry, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, PR China.,Early Intervention Unit, Department of Psychiatry, Affiliated Nanjing Brain Hospital, Nanjing Medical University, Nanjing, Jiangsu, PR China.,Functional Brain Imaging Institute of Nanjing Medical University, Nanjing, Jiangsu, PR China
| | - Zhuang Liu
- School of Public health, China Medical University, Shenyang, Liaoning, PR China
| | - Yange Wei
- Early Intervention Unit, Department of Psychiatry, Affiliated Nanjing Brain Hospital, Nanjing Medical University, Nanjing, Jiangsu, PR China.,Functional Brain Imaging Institute of Nanjing Medical University, Nanjing, Jiangsu, PR China
| | - Yanbo Zhang
- Department of Psychiatry, Faculty of Medicine & Dentistry, University of Alberta, Edmonton, Canada
| | - Fay Y Womer
- Department of Psychiatry, Washington University School of Medicine, St. Louis, USA
| | - Duan Jia
- Early Intervention Unit, Department of Psychiatry, Affiliated Nanjing Brain Hospital, Nanjing Medical University, Nanjing, Jiangsu, PR China.,Functional Brain Imaging Institute of Nanjing Medical University, Nanjing, Jiangsu, PR China
| | - Shengnan Wei
- Department of Psychiatry, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, PR China
| | - Feng Wu
- Department of Psychiatry, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, PR China
| | - Lingtao Kong
- Department of Psychiatry, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, PR China
| | - Xiaowei Jiang
- Department of Psychiatry, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, PR China
| | - Luheng Zhang
- Early Intervention Unit, Department of Psychiatry, Affiliated Nanjing Brain Hospital, Nanjing Medical University, Nanjing, Jiangsu, PR China.,Functional Brain Imaging Institute of Nanjing Medical University, Nanjing, Jiangsu, PR China
| | - Yanqing Tang
- Department of Psychiatry, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, PR China
| | - Xizhe Zhang
- Early Intervention Unit, Department of Psychiatry, Affiliated Nanjing Brain Hospital, Nanjing Medical University, Nanjing, Jiangsu, PR China.,Functional Brain Imaging Institute of Nanjing Medical University, Nanjing, Jiangsu, PR China.,Nanjing Brain Hospital, Medical School, Nanjing University, Nanjing, Jiangsu, PR China.,School of Biomedical Engineering and Informatics, Nanjing Medical University, Nanjing, Jiangsu, PR China
| | - Fei Wang
- Department of Psychiatry, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, PR China.,Early Intervention Unit, Department of Psychiatry, Affiliated Nanjing Brain Hospital, Nanjing Medical University, Nanjing, Jiangsu, PR China.,Functional Brain Imaging Institute of Nanjing Medical University, Nanjing, Jiangsu, PR China.,Nanjing Brain Hospital, Medical School, Nanjing University, Nanjing, Jiangsu, PR China
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Oxidative Stress and Cocaine Intoxication as Start Points in the Pathology of Cocaine-Induced Cardiotoxicity. TOXICS 2021; 9:toxics9120317. [PMID: 34941752 PMCID: PMC8705810 DOI: 10.3390/toxics9120317] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/15/2021] [Revised: 11/12/2021] [Accepted: 11/20/2021] [Indexed: 01/03/2023]
Abstract
Psychomotor stimulants are the most commonly used prohibited substances after cannabis. Globally, their use reaches epidemiological proportions and is one of the most common causes of death in many countries. The use of illicit drugs has negative effects on the cardiovascular system and is one of the causes of serious cardiovascular pathologies, ranging from abnormal heart rhythms to heart attacks and sudden cardiac death. The reactive oxygen species generation, toxic metabolites formation, and oxidative stress play a significant role in cocaine-induced cardiotoxicity. The aim of the present review is to assess acute and chronic cocaine toxicity by focusing on the published literature regarding oxidative stress levels. Hypothetically, this study can serve as a basis for developing a rapid and effective method for determining oxidative stress levels by monitoring changes in the redox status of patients with cocaine intoxication.
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5
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Vanderschuren LJMJ, Ahmed SH. Animal Models of the Behavioral Symptoms of Substance Use Disorders. Cold Spring Harb Perspect Med 2021; 11:cshperspect.a040287. [PMID: 32513674 PMCID: PMC8327824 DOI: 10.1101/cshperspect.a040287] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
To more effectively manage substance use disorders, it is imperative to understand the neural, genetic, and psychological underpinnings of addictive behavior. To contribute to this understanding, considerable efforts have been made to develop translational animal models that capture key behavioral characteristics of addiction on the basis of DSM5 criteria of substance use disorders. In this review, we summarize empirical evidence for the occurrence of addiction-like behavior in animals. These symptoms include escalation of drug use, neurocognitive deficits, resistance to extinction, exaggerated motivation for drugs, increased reinstatement of drug seeking after extinction, preference for drugs over nondrug rewards, and resistance to punishment. The occurrence of addiction-like behavior in laboratory animals has opened the opportunity to investigate the neural, genetic, and psychological background of key aspects of addiction, which may ultimately contribute to the prevention and treatment of substance use disorders.
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Affiliation(s)
- Louk J M J Vanderschuren
- Department of Animals in Science and Society, Division of Behavioural Neuroscience, Faculty of Veterinary Medicine, Utrecht University, 3584 CM Utrecht, the Netherlands
| | - Serge H Ahmed
- Université de Bordeaux, Bordeaux Neurocampus, Institut des Maladies Neurodégénératives, CNRS UMR 5293, F-33000 Bordeaux, France
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6
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Shaffer PM, Rodriguez CP, Gaba A, Byrne T, Casey SC, Harter J, Smelson D. Engaging vulnerable populations in drug treatment court: Six month outcomes from a co-occurring disorder wraparound intervention. INTERNATIONAL JOURNAL OF LAW AND PSYCHIATRY 2021; 76:101700. [PMID: 33864989 DOI: 10.1016/j.ijlp.2021.101700] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Revised: 03/23/2021] [Accepted: 04/09/2021] [Indexed: 06/12/2023]
Abstract
OBJECTIVE Although drug treatment courts (DTCs) have demonstrated positive outcomes, participants with co-occurring mental health and substance use disorders (CODs) are a high-risk group that often struggle with treatment engagement not previously examined. This pilot study fills this gap by looking at six-month behavioral health and criminal justice outcomes among a hard to engage DTC COD participant sample in two Massachusetts DTCs receiving a wraparound-treatment (Maintaining Independence and Sobriety through Systems Integration, Outreach, and Networking-Criminal Justice - MISSION-CJ). METHODS Participants were evaluated at baseline and at six-month follow-up. Bivariate analyses examined baseline differences between clients with higher versus low engagement were examined. A mixed analysis of variance (ANOVA) for repeated measures with time as the within subject factor, and level of engagement as the between subject factor was performed for criminal justice (CJ) and behavioral health outcomes. RESULTS Participants were primarily male (86.6%), White (90.6%), living in unstable housing (86.2%), had an average of 18.94 years of criminal justice involvement, had an average of 15.49 years of regular illicit substance use, and mild mental health symptoms as measured by the BASIS-32 average total score (0.51), with no statistically significant differences at baseline from bivariate analyses. Mixed ANOVA results demonstrated significant effect time of time in MISSION-CJ on reducing nights in jail (p = 0.0266), opioid use (p = 0.0013), and mental health symptom (p = 0.0349). Additional improvements in nights in jail p = 0.0139), illicit substance use (p = 0.0358), and opioid use (p = 0.0013), were observed for clients that had high engagement in MISSION-CJ. CONCLUSIONS Wraparound services, such as MISSION-CJ, alongside DTC programming for a chronic relapsing DTC population can improve engagement in treatment and CJ and behavioral health outcomes. Future research is needed with MISSION-CJ that includes a randomized trial and a larger sample.
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Affiliation(s)
- Paige M Shaffer
- Department of Psychiatry, University of Massachusetts Medical School, Worcester, MA, USA.
| | | | - Ayorkor Gaba
- Department of Psychiatry, University of Massachusetts Medical School, Worcester, MA, USA
| | - Thomas Byrne
- School of Social Work, Boston University, Boston, MA, USA
| | | | - Jennifer Harter
- Department of Psychiatry, University of Massachusetts Medical School, Worcester, MA, USA
| | - David Smelson
- Department of Psychiatry, University of Massachusetts Medical School, Worcester, MA, USA
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7
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Leong SL, Glue P, Manning P, Vanneste S, Lim LJ, Mohan A, De Ridder D. Anterior Cingulate Cortex Implants for Alcohol Addiction: A Feasibility Study. Neurotherapeutics 2020; 17:1287-1299. [PMID: 32323203 PMCID: PMC7641294 DOI: 10.1007/s13311-020-00851-4] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Abnormal neural activity, particularly in the rostrodorsal anterior cingulate cortex (rdACC), appears to be responsible for intense alcohol craving. Neuromodulation of the rdACC using cortical implants may be an option for individuals with treatment-resistant alcohol dependence. This study assessed the effectiveness and feasibility of suppressing alcohol craving using cortical implants of the rdACC using a controlled one-group pre- and post-test study design. Eight intractable alcohol-dependent participants (four males and four females) were implanted with two Lamitrode 44 electrodes over the rdACC bilaterally connected to an internal pulse generator (IPG). The primary endpoint, self-reported alcohol craving reduced by 60.7% (p = 0.004) post- compared to pre-stimulation. Adverse events occurred in four out of the eight participants. Electrophysiology findings showed that among responders, there was a post-stimulation decrease (p = 0.026) in current density at the rdACC for beta 1 band (13-18 Hz). Results suggest that rdACC stimulation using implanted electrodes may potentially be a feasible method for supressing alcohol craving in individuals with severe alcohol use disorder. However, to further establish safety and efficacy, larger controlled clinical trials are needed.
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Affiliation(s)
- Sook Ling Leong
- Trinity College Institute of Neuroscience, Trinity College Dublin, Dublin, Ireland.
- Department of Surgical Sciences, University of Otago, Dunedin, New Zealand.
| | - Paul Glue
- Department of Psychological Medicine, University of Otago, Dunedin, New Zealand
| | - Patrick Manning
- Department of Medicine, University of Otago, Dunedin, New Zealand
| | - Sven Vanneste
- Trinity College Institute of Neuroscience, Trinity College Dublin, Dublin, Ireland
- Lab for Clinical and Integrative Neuroscience, School of Behavioral and Brain Sciences, University of Texas at Dallas, Richardson, TX, USA
| | - Louisa Joyce Lim
- Department of Surgical Sciences, University of Otago, Dunedin, New Zealand
| | - Anusha Mohan
- Trinity College Institute of Neuroscience, Trinity College Dublin, Dublin, Ireland
| | - Dirk De Ridder
- Department of Surgical Sciences, University of Otago, Dunedin, New Zealand.
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8
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Suljević D, Šiljak A, Fočak M. Different outcomes of methadone maintenance therapy in rehabilitated and relapsed drug addicts: significance of liver and renal biomarkers. Drug Chem Toxicol 2020; 45:470-475. [PMID: 32013636 DOI: 10.1080/01480545.2020.1722157] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Abstract
Methadone eliminates heroin use, reduces death rates and criminality associated with heroin use, and improves patients' health and social productivity. This study included long-term addicts who completed a methadone therapy program as well as relapsed patients. Liver and renal markers important for methadone metabolism were analyzed. Renal markers included urea and creatinine, while hepatic markers included total bilirubin, AST, ALT, γGT, and LDH as nonspecific but significant parameters of liver metabolism. The study included 34 male and 6 female heroin-dependent patients undergoing a rehabilitation program with methadone maintenance treatment (MMT). During therapy, average values of all parameters remained within the reference interval but individual parameters in some patients were very high. Significant differences for urea (0.00) and very high individual variations in all parameters, especially γGT and LDH, were found in patients who were in relapse. Age of the patients did not show a correlation with the presence of significant differences in serum biochemical parameters during therapy. Prolonged use of methadone therapy stabilizes high variations of liver and renal markers. MMT achieves a stabilization of serum indicators relevant for methadone metabolism that correlates with the duration of consumption and the type of opioid substance. The most important hepato-renal markers as indicators of therapy success are γGT, LDH, and creatinine. The validity of former enzymatic tests (AST, ALP, and ALT) should be seriously reconsidered in terms of MTT treatment success and monitoring the health of heroin addicts.
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Affiliation(s)
- Damir Suljević
- Department of Biology, Faculty of Science, University of Sarajevo, Sarajevo, Bosnia and Herzegovina
| | - Amra Šiljak
- Department of Biology, Faculty of Science, University of Sarajevo, Sarajevo, Bosnia and Herzegovina
| | - Muhamed Fočak
- Department of Biology, Faculty of Science, University of Sarajevo, Sarajevo, Bosnia and Herzegovina
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9
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Hammond CJ, Allick A, Rahman N, Nanavati J. Structural and Functional Neural Targets of Addiction Treatment in Adolescents and Young Adults: A Systematic Review and Meta-Analysis. J Child Adolesc Psychopharmacol 2019; 29:498-507. [PMID: 31313938 PMCID: PMC6727475 DOI: 10.1089/cap.2019.0007] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Objective: Addictive disorders start during adolescence for most individuals, and developmental differences in brain maturation and response to treatments are present. Recent studies in adults have identified associations between addiction treatment response and regional and circuit specific brain dysfunction, suggesting candidate neural treatment targets. The purpose of this systematic review and meta-analysis was to qualitatively and quantitatively summarize findings from structural and functional neuroimaging studies that examine neural correlates of treatment response in adolescents and young adults with addictive disorders. Methods: A systematic review and meta-analysis of peer-reviewed studies was conducted following PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Studies were selected if they included individuals aged 13-26 with a DSM-IV or DSM-5 (Diagnostic and Statistical Manual, Fourth and Fifth Edition) addictive disorder diagnosis, used neuroimaging, administered a treatment/intervention, and reported within- or between-subject contrasts in brain structure or activity across treatment/intervention and a control condition or brain-behavior correlations with treatment-outcome variables. Quantitative meta-analyses used an activation-likelihood estimation (ALE) approach. Results: Out of 3177 citations, 27 studies were included in the qualitative analysis. Qualitative analyses revealed anatomical, connectivity, and functional brain-behavior associations with response to addiction interventions across a broad array of cortical and subcortical brain regions and associated networks. Eighteen functional magnetic resonance imaging studies involving 354 participants and 88 brain foci were included in the ALE meta-analysis. Despite significant heterogeneity in study design and methods, six ALE activation clusters localized to the anterior cingulate cortex, inferior frontal gyrus, supramarginal gyrus, middle temporal gyrus, precuneus, and putamen showed consistent brain-behavior associations with treatment-outcome variables. Conclusions: Cortical and subcortical brain regions involved in cognition, emotion regulation, decision-making, reward, and self-reference are associated with treatment response in addicted youth. These results are consistent with findings in the adult literature and suggest overlapping neural treatment targets across developmental stages.
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Affiliation(s)
- Christopher J. Hammond
- Division of Child & Adolescent Psychiatry, Johns Hopkins University School of Medicine, Baltimore, Maryland.,Department of Psychiatry & Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland.,Address correspondence to: Christopher J. Hammond, MD, PhD, Division of Child & Adolescent Psychiatry, Johns Hopkins Bayview Medical Center, 5510 Nathan Shock Drive, Baltimore, MD 21224
| | - Aliyah Allick
- Division of Child & Adolescent Psychiatry, Johns Hopkins University School of Medicine, Baltimore, Maryland.,Department of Psychiatry & Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Naisa Rahman
- Division of Child & Adolescent Psychiatry, Johns Hopkins University School of Medicine, Baltimore, Maryland.,Department of Psychiatry & Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Julie Nanavati
- Welch Medical Library, Johns Hopkins University School of Medicine, Baltimore, Maryland
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10
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Uhl GR, Martinez MJ. PTPRD: neurobiology, genetics, and initial pharmacology of a pleiotropic contributor to brain phenotypes. Ann N Y Acad Sci 2019; 1451:112-129. [PMID: 30648269 PMCID: PMC6629525 DOI: 10.1111/nyas.14002] [Citation(s) in RCA: 56] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2018] [Revised: 11/12/2018] [Accepted: 12/19/2018] [Indexed: 12/12/2022]
Abstract
Receptor-type protein tyrosine phosphatase, receptor type D (PTPRD) has likely roles as a neuronal cell adhesion molecule and synaptic specifier. Interest in its neurobiology and genomics has been stimulated by results from human genetics and mouse models for phenotypes related to addiction, restless leg syndrome, neurofibrillary pathology in Alzheimer's disease, cognitive impairment/intellectual disability, mood lability, and obsessive-compulsive disorder. We review PTPRD's discovery, gene family, candidate homomeric and heteromeric binding partners, phosphatase activities, brain distribution, human genetic associations with nervous system phenotypes, and mouse model data relevant to these phenotypes. We discuss the recently reported discovery of the first small molecule inhibitor of PTPRD phosphatase, the identification of its addiction-related effects, and the implications of these findings for the PTPRD-associated brain phenotypes. In assembling PTPRD neurobiology, human genetics, and mouse genetic and pharmacological datasets, we provide a compelling picture of the roles played by PTPRD, its variation, and its potential as a target for novel therapeutics.
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Affiliation(s)
- George R Uhl
- Neurology and Research Services, New Mexico VA Healthcare System, Albuquerque, New Mexico.,Departments of Neurology, Neuroscience, Molecular Genetics and Microbiology, University of New Mexico, Albuquerque, New Mexico.,Biomedical Research Institute of New Mexico, Albuquerque, New Mexico.,Departments of Neurology, Neuroscience and Mental Health, Johns Hopkins Medical Institutions, Baltimore, Maryland
| | - Maria J Martinez
- Neurology and Research Services, New Mexico VA Healthcare System, Albuquerque, New Mexico.,Biomedical Research Institute of New Mexico, Albuquerque, New Mexico
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11
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Milak MS, Pantazatos S, Rashid R, Zanderigo F, DeLorenzo C, Hesselgrave N, Ogden RT, Oquendo MA, Mulhern ST, Miller JM, Burke AK, Parsey RV, Mann JJ. Higher 5-HT 1A autoreceptor binding as an endophenotype for major depressive disorder identified in high risk offspring - A pilot study. Psychiatry Res Neuroimaging 2018; 276:15-23. [PMID: 29702461 PMCID: PMC5959803 DOI: 10.1016/j.pscychresns.2018.04.002] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2016] [Revised: 04/10/2018] [Accepted: 04/12/2018] [Indexed: 01/10/2023]
Abstract
Higher serotonin-1A (5-HT1A) receptor binding potential (BPF) has been found in major depressive disorder (MDD) during and between major depressive episodes. We investigated whether higher 5-HT1A binding is a biologic trait transmitted to healthy high risk (HR) offspring of MDD probands. Data were collected contemporaneously from: nine HR, 30 depressed not-recently medicated (NRM) MDD, 18 remitted NRM MDD, 51 healthy volunteer (HV) subjects. Subjects underwent positron emission tomography (PET) using [11C]WAY100635 to quantify 5-HT1A BPF, estimated using metabolite, free fraction-corrected arterial input function and cerebellar white matter as reference region. Multivoxel pattern analyses (MVPA) of PET data evaluated group status classification of individuals. When tested across 13 regions of interest, an effect of diagnosis is found on BPF which remains significant after correction for sex, age, injected mass and dose: HR have higher BPF than HV (84.3% higher in midbrain raphe, 40.8% higher in hippocampus, mean BPF across all 13 brain regions is 49.9% ± 11.8% higher). Voxel-level BPF maps distinguish HR vs. HV. Elevated 5-HT1A BPF appears to be a familially transmitted trait abnormality. Future studies are needed to replicate this finding in a larger cohort and demonstrate the link to the familial transmission of mood disorders.
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Affiliation(s)
- Matthew S Milak
- Department of Psychiatry, Columbia University, College of Physicians and Surgeons, New York, NY, United States; Molecular Imaging and Neuropathology Division, New York State Psychiatric Institute, New York, NY, United States.
| | - Spiro Pantazatos
- Department of Psychiatry, Columbia University, College of Physicians and Surgeons, New York, NY, United States; Molecular Imaging and Neuropathology Division, New York State Psychiatric Institute, New York, NY, United States
| | - Rain Rashid
- Department of Psychiatry, Columbia University, College of Physicians and Surgeons, New York, NY, United States; Molecular Imaging and Neuropathology Division, New York State Psychiatric Institute, New York, NY, United States
| | - Francesca Zanderigo
- Department of Psychiatry, Columbia University, College of Physicians and Surgeons, New York, NY, United States; Molecular Imaging and Neuropathology Division, New York State Psychiatric Institute, New York, NY, United States
| | | | - Natalie Hesselgrave
- Molecular Imaging and Neuropathology Division, New York State Psychiatric Institute, New York, NY, United States
| | - R Todd Ogden
- Department of Biostatistics, Columbia University, Mailman School of Public Health, New York, NY, United States; Molecular Imaging and Neuropathology Division, New York State Psychiatric Institute, New York, NY, United States
| | - Maria A Oquendo
- Department of Psychiatry, Perelman School of Medicine, United States
| | - Stephanie T Mulhern
- Department of Psychiatry, Columbia University, College of Physicians and Surgeons, New York, NY, United States; Molecular Imaging and Neuropathology Division, New York State Psychiatric Institute, New York, NY, United States
| | - Jeffrey M Miller
- Department of Psychiatry, Columbia University, College of Physicians and Surgeons, New York, NY, United States; Molecular Imaging and Neuropathology Division, New York State Psychiatric Institute, New York, NY, United States
| | - Ainsley K Burke
- Department of Psychiatry, Columbia University, College of Physicians and Surgeons, New York, NY, United States; Molecular Imaging and Neuropathology Division, New York State Psychiatric Institute, New York, NY, United States
| | - Ramin V Parsey
- Department of Psychiatry, Stony Brook Medicine, Stony Brook, New York, United States
| | - J John Mann
- Department of Psychiatry, Columbia University, College of Physicians and Surgeons, New York, NY, United States; Department of Radiology, Columbia University, College of Physicians and Surgeons, New York, NY, United States; Molecular Imaging and Neuropathology Division, New York State Psychiatric Institute, New York, NY, United States
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12
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Abstract
Adolescent substance use disorders (SUDs) are a significant public health issue due to the associated morbidity, mortality, and societal cost. While effective for some adolescents, psychosocial interventions generally produce small-to-moderate reductions in substance use. Most youth relapse within 12 months of treatment. One approach to improve outcomes is through adjunctive pharmacotherapy. Medication assisted treatments have been shown to improve adult SUD treatment outcomes, and preliminary studies in adolescents suggest that combining medication with psychosocial interventions may also enhance SUD outcomes for youth. This article presents a comprehensive review and grading of the evidence from studies conducted in adolescents with SUDs.
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Affiliation(s)
- Christopher J Hammond
- Behavioral Pharmacology Research Unit, Johns Hopkins Bayview Medical Campus, 50 Nathan Shock Drive, Baltimore, MD 21224, USA.
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13
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Koob GF, Volkow ND. Neurobiology of addiction: a neurocircuitry analysis. Lancet Psychiatry 2016; 3:760-773. [PMID: 27475769 PMCID: PMC6135092 DOI: 10.1016/s2215-0366(16)00104-8] [Citation(s) in RCA: 2099] [Impact Index Per Article: 233.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2016] [Revised: 03/09/2016] [Accepted: 03/11/2016] [Indexed: 12/17/2022]
Abstract
Drug addiction represents a dramatic dysregulation of motivational circuits that is caused by a combination of exaggerated incentive salience and habit formation, reward deficits and stress surfeits, and compromised executive function in three stages. The rewarding effects of drugs of abuse, development of incentive salience, and development of drug-seeking habits in the binge/intoxication stage involve changes in dopamine and opioid peptides in the basal ganglia. The increases in negative emotional states and dysphoric and stress-like responses in the withdrawal/negative affect stage involve decreases in the function of the dopamine component of the reward system and recruitment of brain stress neurotransmitters, such as corticotropin-releasing factor and dynorphin, in the neurocircuitry of the extended amygdala. The craving and deficits in executive function in the so-called preoccupation/anticipation stage involve the dysregulation of key afferent projections from the prefrontal cortex and insula, including glutamate, to the basal ganglia and extended amygdala. Molecular genetic studies have identified transduction and transcription factors that act in neurocircuitry associated with the development and maintenance of addiction that might mediate initial vulnerability, maintenance, and relapse associated with addiction.
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Affiliation(s)
- George F Koob
- National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Rockville, MD, USA.
| | - Nora D Volkow
- National Institute on Drug Abuse, National Institutes of Health, Rockville, MD, USA
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14
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Abstract
Opioid use and addiction in adolescents and young adults is a health problem of epidemic proportions, with devastating consequences for youth and their families. Opioid overdose is a life-threatening emergency that should be treated with naloxone, and respiratory support if necessary. Overdose should always be an opportunity to initiate addiction treatment. Detoxification is often a necessary, but never sufficient, component of treatment for OUDs. Treatment for OUDs is effective but treatment capacity is alarmingly limited and under-developed. Emerging consensus supports the incorporation of relapse prevention medications such as buprenorphine and extended release naltrexone into comprehensive psychosocial treatment including counseling and family involvement.
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Affiliation(s)
| | - Ann Bruner
- Mountain Manor Treatment Center, Baltimore, MD, USA; Department of Pediatrics, Johns Hopkins University, Baltimore, MD, USA
| | | | - Marc Fishman
- Mountain Manor Treatment Center, Baltimore, MD, USA; Department of Psychiatry, Johns Hopkins University, Baltimore, MD, USA.
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15
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Segat HJ, Martini F, Barcelos RCS, Brüning CA, Nogueira CW, Burger ME. m-Trifluoromethyl-diphenyldiselenide as a pharmacological tool to treat preference symptoms related to AMPH-induced dependence in rats. Prog Neuropsychopharmacol Biol Psychiatry 2016; 66:1-7. [PMID: 26555614 DOI: 10.1016/j.pnpbp.2015.11.002] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2015] [Revised: 10/26/2015] [Accepted: 11/06/2015] [Indexed: 11/26/2022]
Abstract
Amphetamine (AMPH) abuse is a world concern and a serious public health problem. Repeated administration of high doses of AMPH induces neuropsychiatric consequences, including addiction, reward and psychosis, whose pharmacological treatment has shown limited effectiveness. The m-trifluoromethyl-diphenyldiselenide [(m-CF3-PhSe)2] has been documented as a promising pharmacological agent in different animal models related to oxidative damage. In this study, we examined the influence of (m-CF3-PhSe)2 on withdrawal following re-exposure to AMPH. Wistar rats received d,l-AMPH or saline in the conditioned place preference (CPP) paradigm for 8days. Then, half of each initial (AMPH or saline) experimental group was treated with (m-CF3-PhSe)2 or vehicle, resulting in four final groups: i) Saline/vehicle; ii) (m-CF3-PhSe)2/saline; iii) AMPH/vehicle; and iv) AMPH/(m-CF3-PhSe)2. After fourteen days of (m-CF3-PhSe)2 treatment, animals were re-exposed to AMPH or vehicle in the CPP paradigm for three more days in order to assess drug re-conditioning and memory/locomotor activity, performed 24h after AMPH re-exposure in the CPP and the Y maze, respectively. Subsequently, ex-vivo assays were carried out in samples of the prefrontal cortex (PFC) of the animals. The (m-CF3-PhSe)2 treatment was able to prevent AMPH-induced re-conditioning symptoms in rats. Behavioral observations in the Y maze task showed no significant changes. AMPH exposure was able to increase 5-HT uptake as well as oxidative damage in the PFC, whereas (m-CF3-PhSe)2 treatment exerted a preventative effect against these alterations. The current findings suggest that (m-CF3-PhSe)2 might be considered a promising therapeutic tool for AMPH-induced addiction.
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Affiliation(s)
- H J Segat
- Pós-Graduação em Bioquímica Toxicológica, Universidade Federal de Santa Maria (UFSM), RS, Brazil
| | - F Martini
- Pós-Graduação em Bioquímica Toxicológica, Universidade Federal de Santa Maria (UFSM), RS, Brazil
| | | | - C A Brüning
- Pós-Graduação em Bioquímica Toxicológica, Universidade Federal de Santa Maria (UFSM), RS, Brazil
| | - C W Nogueira
- Pós-Graduação em Bioquímica Toxicológica, Universidade Federal de Santa Maria (UFSM), RS, Brazil.
| | - M E Burger
- Pós-Graduação em Bioquímica Toxicológica, Universidade Federal de Santa Maria (UFSM), RS, Brazil; Pós-Graduação em Farmacologia, UFSM, RS, Brazil.
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16
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Ubaldi M, Cannella N, Ciccocioppo R. Emerging targets for addiction neuropharmacology: From mechanisms to therapeutics. PROGRESS IN BRAIN RESEARCH 2015; 224:251-84. [PMID: 26822362 DOI: 10.1016/bs.pbr.2015.07.018] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Drug abuse represents a considerable burden of disease and has enormous economic impacts on societies. Over the years, few medications have been developed for clinical use. Their utilization is endowed with several limitations, including partial efficacy or significant side effects. On the other hand, the successful advancement of these compounds provides an important proof of concept for the feasibility of drug development programs in addiction. In recent years, a wealth of information has been generated on the psychological mechanisms, genetic or epigenetic predisposing factors, and neurobiological adaptations induced by drug consumption that interact with each other to contribute to disease progression. It is now clear that addiction develops through phases, from initial recreational use to excessive consumption and compulsive drug seeking, with a shift from positive to negative reinforcement driving motivated behaviors. A greater understanding of these mechanisms has opened new vistas in drug development programs. Researchers' attention has been shifted from investigation of classical targets associated with reward to biological substrates responsible for negative reinforcement, impulse loss of control, and maladaptive mechanisms resulting from protracted drug use. From this research, several new biological targets for the development of innovative therapies have started to emerge. This chapter offers an overview of targets currently under scrutiny for the development of new medications for addiction. This work is not exhaustive but rather it provides a few examples of how this research has advanced in recent years by virtue of studies carried out in our laboratory.
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Affiliation(s)
- Massimo Ubaldi
- School of Pharmacy, Pharmacology Unit, University of Camerino, Camerino, Italy
| | - Nazzareno Cannella
- Institute of Psychopharmacology, Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, Mannheim, Germany
| | - Roberto Ciccocioppo
- School of Pharmacy, Pharmacology Unit, University of Camerino, Camerino, Italy.
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17
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Belin D, Belin-Rauscent A, Everitt BJ, Dalley JW. In search of predictive endophenotypes in addiction: insights from preclinical research. GENES BRAIN AND BEHAVIOR 2015; 15:74-88. [DOI: 10.1111/gbb.12265] [Citation(s) in RCA: 105] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/03/2015] [Revised: 10/12/2015] [Accepted: 10/16/2015] [Indexed: 12/13/2022]
Affiliation(s)
- D. Belin
- Department of Pharmacology; University of Cambridge; Cambridge UK
- Behavioural and Clinical Neuroscience Institute; University of Cambridge
| | - A. Belin-Rauscent
- Department of Pharmacology; University of Cambridge; Cambridge UK
- Behavioural and Clinical Neuroscience Institute; University of Cambridge
| | - B. J. Everitt
- Behavioural and Clinical Neuroscience Institute; University of Cambridge
- Department of Psychology; University of Cambridge; Cambridge UK
| | - J. W. Dalley
- Behavioural and Clinical Neuroscience Institute; University of Cambridge
- Department of Psychology; University of Cambridge; Cambridge UK
- Department of Psychiatry; University of Cambridge; Cambridge UK
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18
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Gray JC, MacKillop J. Impulsive delayed reward discounting as a genetically-influenced target for drug abuse prevention: a critical evaluation. Front Psychol 2015; 6:1104. [PMID: 26388788 PMCID: PMC4554956 DOI: 10.3389/fpsyg.2015.01104] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2015] [Accepted: 07/17/2015] [Indexed: 12/22/2022] Open
Abstract
This review evaluates the viability of delayed reward discounting (DRD), an index of how much an individual devalues a future reward based on its delay in time, for genetically-informed drug abuse prevention. A review of the literature suggests that impulsive DRD is robustly associated with drug addiction and meets most of the criteria for being an endophenotype, albeit with mixed findings for specific molecular genetic influences. Several modes of experimental manipulation have been demonstrated to reduce DRD acutely. These include behavioral strategies, such as mindfulness, reward bundling, and episodic future thinking; pharmacological interventions, including noradrenergic agonists, adrenergic agonists, and multiple monoamine agonists; and neuromodulatory interventions, such as transcranial magnetic stimulation and transcranial direct current stimulation. However, the generalization of these interventions to positive clinical outcomes remains unclear and no studies to date have examined interventions on DRD in the context of prevention. Collectively, these findings suggest it would be premature to target DRD for genetically-informed prevention. Indeed, given the evidence of environmental contributions to impulsive DRD, whether genetically-informed secondary prevention would ever be warranted is debatable. Progress in identifying polymorphisms associated with DRD profiles could further clarify the underlying biological systems for pharmacological and neuromodulatory interventions, and, as a qualitatively different risk factor from existing prevention programs, impulsive DRD is worthy of investigation at a more general level as a novel and promising drug abuse prevention target.
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Affiliation(s)
- Joshua C Gray
- Department of Psychology, University of Georgia , Athens, GA, USA
| | - James MacKillop
- Department of Psychology, University of Georgia , Athens, GA, USA ; Peter Boris Centre for Addictions Research, McMaster University/St. Joseph's Healthcare Hamilton , Hamilton, ON, Canada
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19
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Forero DA, Vélez-van-Meerbeke A, Deshpande SN, Nicolini H, Perry G. Neuropsychiatric genetics in developing countries: Current challenges. World J Psychiatry 2014; 4:69-71. [PMID: 25540721 PMCID: PMC4274588 DOI: 10.5498/wjp.v4.i4.69] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2014] [Revised: 11/27/2014] [Accepted: 12/10/2014] [Indexed: 02/05/2023] Open
Abstract
Neuropsychiatric disorders (NPDs) constitute a heavy burden on public health systems around the world and studies have demonstrated that the negative impact of NPDs is larger in Low and Middle Income Countries (LMICs). In recent decades, several studies have come to the understanding that genetic factors play a major role in the risk for a large number of NPDs. However, few neuropsychiatric genetics studies have been published from LMICs. In this Editorial, we discuss important issues impinging on advances in neuropsychiatric genetics research in LMICs. It is essential that scientists educate policymakers and officials of funding agencies on the importance of providing adequate funding for research in these areas. Development of local well-supported research programs focused on NPD genetics should be an important asset to develop; it would facilitate the establishment of sustainable research efforts that could lead to appropriate diagnosis and specific, affordable and feasible interventions in LMICs. It is important to point out that research into the biological basis of human NPDs is not only an academic effort reserved for a few elite institutions in economically developed countries, but it is vitally important for the mental health of people around the world.
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20
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Study of five novel non-synonymous polymorphisms in human brain-expressed genes in a Colombian sample. Ann Neurosci 2014; 21:138-43. [PMID: 25452674 PMCID: PMC4248474 DOI: 10.5214/ans.0972.7531.210405] [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: 01/29/2014] [Revised: 05/16/2014] [Accepted: 07/10/2014] [Indexed: 11/29/2022] Open
Abstract
Background Non-synonymous single nucleotide polymorphisms (nsSNPs) in brain-expressed genes represent interesting candidates for genetic research in neuropsychiatric disorders. Purpose To study novel nsSNPs in brain-expressed genes in a sample of Colombian subjects. Methods We applied an approach based on in silico mining of available genomic data to identify and select novel nsSNPs in brain-expressed genes. We developed novel genotyping assays, based in allele-specific PCR methods, for these nsSNPs and genotyped them in 171 Colombian subjects. Results Five common nsSNPs (rs6855837; p.Leu395Ile, rs2305160; p.Thr394Ala, rs10503929; p.Met289Thr, rs2270641; p.Thr4Pro and rs3822659; p.Ser735Ala) were studied, located in the CLOCK, NPAS2, NRG1, SLC18A1 and WWC1 genes. We reported allele and genotype frequencies in a sample of South American healthy subjects. There is previous experimental evidence, arising from genome-wide expression and association studies, for the involvement of these genes in several neuropsychiatric disorders and endophenotypes, such as schizophrenia, mood disorders or memory performance. Conclusions Frequencies for these nsSNPSs in the Colombian samples varied in comparison to different HapMap populations. Future study of these nsSNPs in brain-expressed genes, a synaptogenomics approach, will be important for a better understanding of neuropsychiatric diseases and endophenotypes in different populations.
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21
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Gullo MJ, Potenza MN. Impulsivity: mechanisms, moderators and implications for addictive behaviors. Addict Behav 2014; 39:1543-1546. [PMID: 25042111 DOI: 10.1016/j.addbeh.2014.06.005] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2014] [Accepted: 06/12/2014] [Indexed: 12/21/2022]
Affiliation(s)
- Matthew J Gullo
- Centre for Youth Substance Abuse Research, The University of Queensland, Australia.
| | - Marc N Potenza
- Department of Psychiatry, Yale University School of Medicine, New Haven, CT, United States; Department of Neurobiology, Yale University School of Medicine, New Haven, CT, United States; Child Study Center, Yale University School of Medicine, New Haven, CT, United States
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22
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Pharmacological inactivation of the prelimbic cortex emulates compulsive reward seeking in rats. Brain Res 2014; 1628:210-8. [PMID: 25451128 DOI: 10.1016/j.brainres.2014.10.045] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2014] [Accepted: 10/22/2014] [Indexed: 11/22/2022]
Abstract
Drug addiction is a chronic, relapsing brain disorder characterized by compulsive drug use. Contemporary addiction theories state that loss of control over drug use is mediated by a combination of several processes, including a transition from goal-directed to habitual forms of drug seeking and taking, and a breakdown of the prefrontally-mediated cognitive control over drug intake. In recent years, substantial progress has been made in the modelling of loss of control over drug use in animal models, but the neural substrates of compulsive drug use remain largely unknown. On the basis of their involvement in goal-directed behaviour, value-based decision making, impulse control and drug seeking behaviour, we identified the prelimbic cortex (PrL) and orbitofrontal cortex (OFC) as candidate regions to be involved in compulsive drug seeking. Using a conditioned suppression model, we have previously shown that prolonged cocaine self-administration reduces the ability of a conditioned aversive stimulus to reduce drug seeking, which may reflect the unflagging pursuit of drugs in human addicts. Therefore, we tested the hypothesis that dysfunction of the PrL and OFC underlies loss of control over drug seeking behaviour, apparent as reduced conditioned suppression. Pharmacological inactivation of the PrL, using the GABA receptor agonists baclofen and muscimol, reduced conditioned suppression of cocaine and sucrose seeking in animals with limited self-administration experience. Inactivation of the OFC did not influence conditioned suppression, however. These data indicate that reduced neural activity in the PrL promotes persistent seeking behaviour, which may underlie compulsive aspects of drug use in addiction.
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23
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Rossetti C, Halfon O, Boutrel B. Controversies about a common etiology for eating and mood disorders. Front Psychol 2014; 5:1205. [PMID: 25386150 PMCID: PMC4209809 DOI: 10.3389/fpsyg.2014.01205] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2014] [Accepted: 10/06/2014] [Indexed: 12/25/2022] Open
Abstract
Obesity and depression represent a growing health concern worldwide. For many years, basic science and medicine have considered obesity as a metabolic illness, while depression was classified a psychiatric disorder. Despite accumulating evidence suggesting that obesity and depression may share commonalities, the causal link between eating and mood disorders remains to be fully understood. This etiology is highly complex, consisting of multiple environmental and genetic risk factors that interact with each other. In this review, we sought to summarize the preclinical and clinical evidence supporting a common etiology for eating and mood disorders, with a particular emphasis on signaling pathways involved in the maintenance of energy balance and mood stability, among which orexigenic and anorexigenic neuropeptides, metabolic factors, stress responsive hormones, cytokines, and neurotrophic factors.
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Affiliation(s)
- Clara Rossetti
- Center for Psychiatric Neuroscience, Lausanne University Hospital Lausanne, Switzerland
| | - Olivier Halfon
- Division of Child and Adolescent Psychiatry, Department of Psychiatry, Lausanne University Hospital Lausanne, Switzerland
| | - Benjamin Boutrel
- Center for Psychiatric Neuroscience, Lausanne University Hospital Lausanne, Switzerland ; Division of Child and Adolescent Psychiatry, Department of Psychiatry, Lausanne University Hospital Lausanne, Switzerland
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24
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Homberg JR, Karel P, Verheij MMM. Individual differences in cocaine addiction: maladaptive behavioural traits. Addict Biol 2014; 19:517-28. [PMID: 24835358 DOI: 10.1111/adb.12036] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
Cocaine use leads to addiction in only a subset of individuals. Understanding the mechanisms underlying these individual differences in the transition from cocaine use to cocaine abuse is important to develop treatment strategies. There is agreement that specific behavioural traits increase the risk for addiction. As such, both high impulsivity and high anxiety have been reported to predict (compulsive) cocaine self-administration behaviour. Here, we set out a new view explaining how these two behavioural traits may affect addictive behaviour. According to psychological and psychiatric evolutionary views, organisms flourish well when they fit (match) their environment by trait and genotype. However, under non-fit conditions, the need to compensate the failure to deal with this environment increases, and, as a consequence, the functional use of rewarding drugs like cocaine may also increase. It suggests that neither impulsivity nor anxiety are bad per se, but that the increased risk to develop cocaine addiction is dependent on whether behavioural traits are adaptive or maladaptive in the environment to which the animals are exposed. This 'behavioural (mal)adaptation view' on individual differences in vulnerability to cocaine addiction may help to improve therapies for addiction.
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Affiliation(s)
- Judith R. Homberg
- Department of Cognitive Neuroscience, Radboud University Nijmegen Medical Centre; Donders Institute for Brain, Cognition, and Behaviour, Centre for Neuroscience; Nijmegen The Netherlands
| | - Peter Karel
- Department of Cognitive Neuroscience, Radboud University Nijmegen Medical Centre; Donders Institute for Brain, Cognition, and Behaviour, Centre for Neuroscience; Nijmegen The Netherlands
| | - Michel M. M. Verheij
- Department of Cognitive Neuroscience, Radboud University Nijmegen Medical Centre; Donders Institute for Brain, Cognition, and Behaviour, Centre for Neuroscience; Nijmegen The Netherlands
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25
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McCormack RP, Hoffman LF, Norman M, Goldfrank LR, Norman EM. Voices of homeless alcoholics who frequent Bellevue Hospital: a qualitative study. Ann Emerg Med 2014; 65:178-86.e6. [PMID: 24976534 DOI: 10.1016/j.annemergmed.2014.05.025] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2014] [Revised: 04/17/2014] [Accepted: 05/05/2014] [Indexed: 11/17/2022]
Abstract
STUDY OBJECTIVE We describe the evolution, environment, and psychosocial context of alcoholism from the perspective of chronically homeless, alcohol-dependent, frequent emergency department (ED) attendees. We use their words to explore how homelessness, health care, and other influences have contributed to the cause, progression, and management of their alcoholism. METHODS We conducted detailed, semistructured, qualitative interviews, using a phenomenological approach with 20 chronically homeless, alcohol-dependent participants who had greater than 4 annual ED visits for 2 consecutive years at Bellevue Hospital in New York City. We used an administrative database and purposive sampling to obtain typical and atypical cases with diverse backgrounds. Interviews were audio recorded and transcribed verbatim. We triangulated interviews, field notes, and medical records. We used ATLAS.ti to code and determine themes, which we reviewed for agreement. We bracketed for researcher bias and maintained an audit trail. RESULTS Interviews lasted an average of 50 minutes and yielded 800 pages of transcript. Fifty codes emerged, which were clustered into 4 broad themes: alcoholism, homelessness, health care, and the future. The participants' perspectives support a multifactorial process for the evolution of their alcoholism and its bidirectional reinforcing relationship with homelessness. Their self-efficacy and motivation for treatment is eroded by their progressive sense of hopelessness, which provides context for behaviors that reinforce stigma. CONCLUSION Our study exposes concepts for further exploration in regard to the difficulty in engaging individuals who are incapable of envisioning a future. We hypothesize that a multidisciplinary harm reduction approach that integrates health and social services is achievable and would address their needs more effectively.
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Affiliation(s)
- Ryan P McCormack
- Department of Emergency Medicine, New York University School of Medicine, New York, NY.
| | - Lily F Hoffman
- Department of Emergency Medicine, New York University School of Medicine, New York, NY; New York University Gallatin School of Individualized Study, New York, NY
| | - Michael Norman
- Department of Emergency Medicine, New York University School of Medicine, New York, NY; Arthur L. Carter Journalism Institute, New York University College of Arts and Sciences, New York, NY
| | - Lewis R Goldfrank
- Department of Emergency Medicine, New York University School of Medicine, New York, NY
| | - Elizabeth M Norman
- Department of Emergency Medicine, New York University School of Medicine, New York, NY; Department of Humanities and Social Sciences and Interdepartmental Research Studies, New York University Steinhardt School of Culture, Education, and Human Development, New York, NY
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26
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Linares OA, Daly D, Stefanovski D, Boston RC. The CYP2D6 gene determines oxycodone's phenotype-specific addictive potential: implications for addiction prevention and treatment. Med Hypotheses 2014; 82:390-4. [PMID: 24495562 DOI: 10.1016/j.mehy.2014.01.010] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2013] [Revised: 01/06/2014] [Accepted: 01/13/2014] [Indexed: 10/25/2022]
Abstract
We propose a hypothesis for predicting addictive potential of oral drugs, in general, and oxycodone's addictive potential, in particular. We hypothesize that a patient's CYP2D6 phenotype determines oxycodone's addictive potential, in part, via genotype-specific regulation of its clearance; although, other possible modulators of oxycodone's addiction potential exist. For example, brain CYPs related to phenotype could be involved. To pilot test our hypothesis, we used a mathematical model which postulates that oxycodone's addictive potential is given by: LAP=E/(ka/ke), where LAP represents addictive potential, E represents euphoric potency, ka is the absorption rate constant of drug from the gastrointestinal tract, and ke is the systemic elimination rate constant of drug by all processes responsible for its removal from plasma. Using CYP2D6 phenotype-specific oxycodone pharmacokinetic parameter values derived from published data, our hypothesis predicted that the canonical order of oxycodone's addictive potential was UM>EM>IM>PM, with corresponding LAP values of 0.24, 0.21, 0.17, and 0.15 respectively. Our hypothesis about oxycodone's addictive potential may provide a unifying approach useful for both personalized medicine dosing and predicting addictive potential of oral drugs in humans, since it is based on both oxycodone's pharmacogenetics and pharmacokinetics.
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Affiliation(s)
- Oscar A Linares
- Plymouth Pharmacokinetic Modeling Study Group, 46425 Southview Lane, Plymouth, MI 48170, USA.
| | - David Daly
- Plymouth Pharmacokinetic Modeling Study Group, 46425 Southview Lane, Plymouth, MI 48170, USA
| | - Darko Stefanovski
- Cedars-Sinai Medical Center, Biomedical Sciences Division, 8700 Beverly Boulevard, West Hollywood, CA 90048, USA
| | - Raymond C Boston
- Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, 3600 Market Street, Philadelphia, PA 19104-2646, USA
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Planeta CS, Lepsch LB, Alves R, Scavone C. Influence of the dopaminergic system, CREB, and transcription factor-κB on cocaine neurotoxicity. Braz J Med Biol Res 2013; 46:909-915. [PMID: 24141554 PMCID: PMC3854330 DOI: 10.1590/1414-431x20133379] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2013] [Accepted: 08/19/2013] [Indexed: 01/04/2023] Open
Abstract
Cocaine is a widely used drug and its abuse is associated with physical, psychiatric
and social problems. Abnormalities in newborns have been demonstrated to be due to
the toxic effects of cocaine during fetal development. The mechanism by which cocaine
causes neurological damage is complex and involves interactions of the drug with
several neurotransmitter systems, such as the increase of extracellular levels of
dopamine and free radicals, and modulation of transcription factors. The aim of this
review was to evaluate the importance of the dopaminergic system and the
participation of inflammatory signaling in cocaine neurotoxicity. Our study showed
that cocaine activates the transcription factors NF-κB and CREB, which regulate genes
involved in cellular death. GBR 12909 (an inhibitor of dopamine reuptake), lidocaine
(a local anesthetic), and dopamine did not activate NF-κB in the same way as cocaine.
However, the attenuation of NF-κB activity after the pretreatment of the cells with
SCH 23390, a D1 receptor antagonist, suggests that the activation of NF-κB by cocaine
is, at least partially, due to activation of D1 receptors. NF-κB seems to have a
protective role in these cells because its inhibition increased cellular death caused
by cocaine. The increase in BDNF (brain-derived neurotrophic factor) mRNA can also be
related to the protective role of both CREB and NF-κB transcription factors. An
understanding of the mechanisms by which cocaine induces cell death in the brain will
contribute to the development of new therapies for drug abusers, which can help to
slow down the progress of degenerative processes.
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Affiliation(s)
- C S Planeta
- Universidade Estadual Paulista, Laboratório de Neuropsicofarmacologia, Faculdade de Ciências Farmacêuticas, AraraquaraSP, Brasil
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Rubinstein ML, Shiffman S, Rait MA, Benowitz NL. Race, gender, and nicotine metabolism in adolescent smokers. Nicotine Tob Res 2013; 15:1311-5. [PMID: 23239845 PMCID: PMC3682846 DOI: 10.1093/ntr/nts272] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2012] [Accepted: 10/29/2012] [Indexed: 11/13/2022]
Abstract
INTRODUCTION Differences in the rate of nicotine metabolism between genders and different races have been hypothesized to contribute to disparities in smoking rate, susceptibility to addiction, and ability to quit smoking. The purpose of this study was to determine the effect of race and gender on the rate of nicotine metabolism as indicated by the nicotine metabolite ratio (NMR) in adolescent smokers. METHODS One hundred and fifty-nine adolescent smokers aged 13-17 were given 2mg of deuterium-labeled cotinine (cotinine-d4). The NMR was calculated as the ratio of concentrations of deuterium-labeled 3'-hydroxycotinine (ng/ml) to cotinine-d4 (ng/ml) in saliva and is a validated biomarker of the rate of nicotine metabolism. RESULTS The sample was 67.3% female and racially mixed. On average, Whites had the fastest rates of metabolism compared with both Blacks/African Americans (p < .01) and Asians (p = .01). The NMR was similar between males and females (p = .70). Among the 19 girls who reported using estrogen-containing contraceptives, there was no significant difference in NMR compared with the 83 girls who did not use contraceptives (p = .24) or the 10 who used progestin-only contraceptives (p = .45). CONCLUSIONS Among adolescent smokers, racial variations in rates of nicotine metabolism were similar to those that have been reported in adult smokers. In contrast to findings in adult smokers, the NMR did not vary significantly by gender or self-reported hormone use.
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Affiliation(s)
- Mark L Rubinstein
- Division of Adolescent Medicine, University of California, San Francisco, San Francisco, CA 94118, USA.
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29
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Lesscher HMB, Vanderschuren LJMJ. Compulsive drug use and its neural substrates. Rev Neurosci 2013; 23:731-45. [PMID: 23079511 DOI: 10.1515/revneuro-2012-0066] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2012] [Accepted: 08/15/2012] [Indexed: 12/22/2022]
Abstract
Drug addiction is a chronic relapsing brain disease, characterized by compulsive drug use. Despite the fact that drug addiction affects millions of people worldwide, treatments for this disorder are limited in number and efficacy. In our opinion, understanding the neural underpinnings of drug addiction would open new avenues for the development of innovative treatments for this disorder. Based on an awareness that drug use and drug reward do not equal drug addiction, there has been increasing interest in developing animal models of addiction that mimick the loss of control over drug use more closely than existing models aimed at studying drug reward. The present review provides an overview of animal studies of compulsive drug use and the neural mechanisms involved. First, the employed models are summarized, with a particular emphasis on models of escalation of drug use and resistance to punishment. Next, we discuss mechanisms within the (ventral and dorsal) striatum and (central) amygdala that have recently been implicated in the compulsive seeking and taking of alcohol and cocaine. The studies discussed here provide a promising line of research that will advance our knowledge of the neural circuits involved in the self-destructive behavior that characterizes drug addiction.
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Affiliation(s)
- Heidi M B Lesscher
- Department of Animals in Science and Society, Utrecht University, Utrecht, The Netherlands
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30
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Schulte-van Maaren YWM, Carlier IVE, Giltay EJ, van Noorden MS, de Waal MWM, van der Wee NJA, Zitman FG. Reference values for mental health assessment instruments: objectives and methods of the Leiden Routine Outcome Monitoring Study. J Eval Clin Pract 2013; 19:342-50. [PMID: 22332898 DOI: 10.1111/j.1365-2753.2012.01830.x] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
RATIONALE, AIMS AND OBJECTIVES Routine outcome monitoring (ROM) was developed to establish the outcome of psychotherapeutic and pharmacological treatments through repeated assessments before, during and after treatment. Although standardization of psychiatric assessments and their reference values are essential for patient care, for various ROM instruments reference values are not available. The aim of the Leiden ROM Study is to generate reference values for 22 ROM instruments, covering generic and specific mood, anxiety and somatoform (MAS) disorders, for the general population. This article describes the extensive process of recruitment, as well as baseline characteristics of patient versus non-patient groups. METHOD Cross-sectional study in randomly selected participants aged 18-65 years from the Dutch population, included through general practitioners. RESULTS Extensive demographic, psychosocial, mental health, and biological data from 1302 participants, recruited via general practitioners, were collected during a two-hour standardized assessment including observer-rated and self-report scales. These data will be compared with corresponding data from 7840 patients with psychopathology who were referred to secondary care. On-going quality control and calibration ensured maintenance of high quality during data collection. CONCLUSIONS This reference group study for mental health assessments is the first study of this size carried out in the Netherlands. The results of this study are expected to be of value to secondary psychiatric care because they allow the indication of progress in health, treatment effect and possible termination of treatment. Additionally, the reference values can be used by primary care physicians as decision threshold for referral to specialized mental health care and vice versa.
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31
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Abstract
It is increasingly recognized that studying drug taking in laboratory animals does not equate to studying genuine addiction, characterized by loss of control over drug use. This has inspired recent work aimed at capturing genuine addiction-like behavior in animals. In this work, we summarize empirical evidence for the occurrence of several DSM-IV-like symptoms of addiction in animals after extended drug use. These symptoms include escalation of drug use, neurocognitive deficits, resistance to extinction, increased motivation for drugs, preference for drugs over nondrug rewards, and resistance to punishment. The fact that addiction-like behavior can occur and be studied in animals gives us the exciting opportunity to investigate the neural and genetic background of drug addiction, which we hope will ultimately lead to the development of more effective treatments for this devastating disorder.
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Affiliation(s)
- Louk J M J Vanderschuren
- Department of Animals in Science and Society, Division of Behavioural Neuroscience, Faculty of Veterinary Medicine, Utrecht University, 3584 CG Utrecht, The Netherlands.
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32
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Potenza MN. Biological contributions to addictions in adolescents and adults: prevention, treatment, and policy implications. J Adolesc Health 2013; 52:S22-32. [PMID: 23332567 PMCID: PMC3935152 DOI: 10.1016/j.jadohealth.2012.05.007] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2012] [Revised: 05/22/2012] [Accepted: 05/22/2012] [Indexed: 01/23/2023]
Abstract
PURPOSE Despite significant advances in our understanding of the biological bases of addictions, these disorders continue to represent a huge public health burden that is associated with substantial personal suffering. Efforts to target addictions require consideration of how the improved biological understanding of addictions may lead to improved prevention, treatment, and policy initiatives. METHOD In this article, we provide a narrative review of current biological models for addictions with a goal of placing existing data and theories within a translational and developmental framework targeting the advancement of prevention, treatment, and policy strategies. RESULTS Data regarding individual differences, intermediary phenotypes, and main and interactive influences of genetic and environmental contributions in the setting of developmental trajectories that may be influenced by addictive drugs or behavior indicate complex underpinnings of addictions. CONCLUSIONS Consideration and further elucidation of the biological etiologies of addictions hold significant potential for making important gains and reducing the public health impact of addictions.
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Affiliation(s)
- Marc N Potenza
- Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut; Department of Neurobiology, Yale University School of Medicine, New Haven, Connecticut; Child Study Center, Yale University School of Medicine, New Haven, Connecticut.
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Mathews R, Hall W, Carter A. Direct-to-consumer genetic testing for addiction susceptibility: a premature commercialisation of doubtful validity and value. Addiction 2012; 107:2069-74. [PMID: 22510165 DOI: 10.1111/j.1360-0443.2012.03836.x] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Genetic research on addiction liability and pharmacogenetic research on treatments for addiction have identified some genetic variants associated with disease risk and treatment. Genetic testing for addiction liability and treatment response has not been used widely in clinical practice because most of the genes identified only modestly predict addiction risk or treatment response. However, many of these genetic tests have been commercialized prematurely and are available direct to the consumer (DTC). The easy availability of DTC tests for addiction liability and lack of regulation over their use raises a number of ethical concerns. Of paramount concern is the limited predictive power and clinical utility of these tests. Many DTC testing companies do not provide the consumer with the necessary genetic counselling to assist them in interpreting and acting on their test results. They may also engage in misleading marketing to entice consumers to purchase their products. Consumers' genetic information may be vulnerable to misuse by third parties, as there are limited standards to protect the privacy of the genetic information. Non-consensual testing and inappropriate testing of minors may also occur. The United States Food and Drug Administration plans to regulate DTC genetic tests. Based on the ethical concerns we discuss below, we believe there is a strong case for regulation of DTC genetic tests for addiction liability and treatment response. We argue that until this occurs, these tests have more potential to cause harm than to contribute to improved prevention and treatment of addiction.
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Affiliation(s)
- Rebecca Mathews
- The University of Queensland, UQ Centre for Clinical Research, Queensland, Australia
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Green KM, Zebrak KA, Fothergill KE, Robertson JA, Ensminger ME. Childhood and adolescent risk factors for comorbid depression and substance use disorders in adulthood. Addict Behav 2012; 37:1240-7. [PMID: 22762959 DOI: 10.1016/j.addbeh.2012.06.008] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2012] [Revised: 05/29/2012] [Accepted: 06/06/2012] [Indexed: 12/13/2022]
Abstract
The comorbidity of major depression and substance use disorders is well documented. However, thorough understanding of prevalence and early risk factors for comorbidity in adulthood is lacking, particularly among urban African Americans. With data from the Woodlawn Study, which follows a community cohort of urban African Americans from ages 6 to 42, we identify the prevalence of comorbidity and childhood and adolescent risk factors of comorbid depression and substance use disorders, depression alone, and substance use disorders alone. Prevalence of comorbid substance use disorders and major depression in adulthood is 8.3% overall. Comorbidity in cohort men is twice that for women (11.1% vs. 5.7%). Adjusted multinomial regression models found few differences in risk factors for comorbidity compared to either major depression or a substance use disorder on its own. However, results do suggest distinct risk factors for depression without a substance use disorder in adulthood compared to a substance use disorder without depression in adulthood. In particular, low socioeconomic status and family conflict was related to increased risk of developing major depression in adulthood, while dropping out of high school was a statistically significant predictor of adult-onset substance use disorders. Early onset of marijuana use differentiated those with a substance use disorder with or without depression from those with depression without a substance use disorder in adjusted models. In conclusion, comorbid substance use disorders and depression are highly prevalent among these urban African Americans. Insight into the unique childhood and adolescent risk factors for depression compared to substance use disorders is critical to intervention development in urban communities. Results suggest that these programs must consider individual behaviors, as well as the early family dynamic.
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Affiliation(s)
- Kerry M Green
- University of Maryland School of Public Health, Department of Behavioral and Community Health, 2387 SPH Building, Valley Drive, College Park, MD 20742, United States.
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MacDonald ML, Ciccimaro E, Prakash A, Banerjee A, Seeholzer SH, Blair IA, Hahn CG. Biochemical fractionation and stable isotope dilution liquid chromatography-mass spectrometry for targeted and microdomain-specific protein quantification in human postmortem brain tissue. Mol Cell Proteomics 2012; 11:1670-81. [PMID: 22942359 DOI: 10.1074/mcp.m112.021766] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Synaptic architecture and its adaptive changes require numerous molecular events that are both highly ordered and complex. A majority of neuropsychiatric illnesses are complex trait disorders, in which multiple etiologic factors converge at the synapse via many signaling pathways. Investigating the protein composition of synaptic microdomains from human patient brain tissues will yield valuable insights into the interactions of risk genes in many disorders. These types of studies in postmortem tissues have been limited by the lack of proper study paradigms. Thus, it is necessary not only to develop strategies to quantify protein and post-translational modifications at the synapse, but also to rigorously validate them for use in postmortem human brain tissues. In this study we describe the development of a liquid chromatography-selected reaction monitoring method, using a stable isotope-labeled neuronal proteome standard prepared from the brain tissue of a stable isotope-labeled mouse, for the multiplexed quantification of target synaptic proteins in mammalian samples. Additionally, we report the use of this method to validate a biochemical approach for the preparation of synaptic microdomain enrichments from human postmortem prefrontal cortex. Our data demonstrate that a targeted mass spectrometry approach with a true neuronal proteome standard facilitates accurate and precise quantification of over 100 synaptic proteins in mammalian samples, with the potential to quantify over 1000 proteins. Using this method, we found that protein enrichments in subcellular fractions prepared from human postmortem brain tissue were strikingly similar to those prepared from fresh mouse brain tissue. These findings demonstrate that biochemical fractionation methods paired with targeted proteomic strategies can be used in human brain tissues, with important implications for the study of neuropsychiatric disease.
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Affiliation(s)
- Matthew L MacDonald
- Department of Psychiatry, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19104, USA
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36
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Abstract
This article discusses recent findings on the neurobiology of pediatric depression as well as the interplay between genetic and environmental factors in determining the risk for the disorder. Utilizing data from both animal and human studies, the authors focus on the evolving understanding of the developmental neurobiology of emotional regulation, cognitive function and social behavior as it applies to the risk and clinical course of depression. Treatment implications and directions for future research are also discussed.
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Affiliation(s)
- John M. Weir
- Center for Molecular and Behavioral Neuroscience, Meharry Medical College, Nashville Tennessee
| | - Arthurine Zakama
- Vanderbilt University, Nashville, Tennessee, Nashville Tennessee
| | - Uma Rao
- Center for Molecular and Behavioral Neuroscience, Meharry Medical College, Nashville Tennessee
- Vanderbilt University, Nashville, Tennessee, Nashville Tennessee
- Department of Psychiatry and Behavioral Sciences, Meharry Medical College, Nashville Tennessee
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Yang BZ, Han S, Kranzler HR, Farrer LA, Gelernter J. A genomewide linkage scan of cocaine dependence and major depressive episode in two populations. Neuropsychopharmacology 2011; 36:2422-30. [PMID: 21849985 PMCID: PMC3194068 DOI: 10.1038/npp.2011.122] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
Cocaine dependence (CD) and major depressive episode (MDE) frequently co-occur with poorer treatment outcome and higher relapse risk. Shared genetic risk was affirmed; to date, there have been no reports of genomewide linkage scans (GWLSs) surveying the susceptibility regions for comorbid CD and MDE (CD-MDE). We aimed to identify chromosomal regions and candidate genes susceptible to CD, MDE, and CD-MDE in African Americans (AAs) and European Americans (EAs). A total of 1896 individuals were recruited from 384 AA and 355 EA families, each with at least a sibling-pair with CD and/or opioid dependence. Array-based genotyping of about 6000 single-nucleotide polymorphisms was completed for all individuals. Parametric and non-parametric genomewide linkage analyses were performed. We found a genomewide-significant linkage peak on chromosome 7 at 183.4 cM for non-parametric analysis of CD-MDE in AAs (lod=3.8, genomewide empirical p=0.016; point-wise p=0.00001). A nearly genomewide significant linkage was identified for CD-MDE in EAs on chromosome 5 at 14.3 cM (logarithm of odds (lod)=2.95, genomewide empirical p=0.055; point-wise p=0.00012). Parametric analysis corroborated the findings in these two regions and improved the support for the peak on chromosome 5 so that it reached genomewide significance (heterogeneity lod=3.28, genomewide empirical p=0.046; point-wise p=0.00053). This is the first GWLS for CD-MDE. The genomewide significant linkage regions on chromosomes 5 and 7 harbor four particularly promising candidate genes: SRD5A1, UBE3C, PTPRN2, and VIPR2. Replication of the linkage findings in other populations is warranted, as is a focused analysis of the genes located in the linkage regions implicated here.
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Affiliation(s)
- Bao-Zhu Yang
- Department of Psychiatry, Yale University School of Medicine, New Haven, and VA CT Healthcare Center, West Haven, CT, USA
| | - Shizhong Han
- Department of Psychiatry, Yale University School of Medicine, New Haven, and VA CT Healthcare Center, West Haven, CT, USA
| | - Henry R Kranzler
- Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, USA
| | - Lindsay A Farrer
- Department of Medicine, Neurology, Ophthalmology, Genetics and Genomics, Epidemiology and Biostatistics, Boston University Schools of Medicine and Public Health, Boston, MA, USA
| | - Joel Gelernter
- Department of Psychiatry, Yale University School of Medicine, New Haven, and VA CT Healthcare Center, West Haven, CT, USA,Department of Genetics and Neurobiology, Yale University School of Medicine, New Haven, and VA CT Healthcare Center, West Haven, CT, USA,Division of Human Genetics in Psychiatry, Department of Psychiatry, Yale University School of Medicine, New Haven and VA CT Healthcare Center, VA CT 116A2, 950 Campbell Avenue, West Haven, CT 06516, USA, Tel: +1 203 932 5711, Fax: +1 203 937 4741, E-mail:
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The science of making drug-addicted animals. Neuroscience 2011; 211:107-25. [PMID: 21864653 DOI: 10.1016/j.neuroscience.2011.08.014] [Citation(s) in RCA: 128] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2011] [Revised: 08/03/2011] [Accepted: 08/04/2011] [Indexed: 12/13/2022]
Abstract
Research involving animal models of drug addiction can be viewed as a sort of reverse psychiatry. Contrary to clinicians who seek to treat addicted people to become and remain abstinent, researchers seek to make drug-naïve animals addicted to a drug with known addictive properties in humans. The goals of this research are to better understand the neuroscience of drug addiction and, ultimately, to translate this knowledge into effective treatments for people with addiction. The present review will not cover the vast literature that has accumulated over the past 50 years on animal models of drug addiction. It is instead more modestly devoted to recent research spanning the past decade on drug self-administration-based models of addiction in the rat (the animal species most frequently used in the field), with a special focus on current efforts to model compulsive cocaine use as opposed to nonaddictive use. Surprisingly, it turns out that modeling compulsive cocaine use in rats is possible but more difficult than previously thought. In fact, it appears that resilience to cocaine addiction is the norm in rats. As in human cocaine users, only few individual rats would be vulnerable. This conclusion has several important implications for future research on the neuroscience of cocaine addiction and on preclinical medication development.
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Abstract
The process of addiction is often studied in the neurosciences as a function of the quantity or type of substance consumed, with the ultimate goal of counteracting these effects by other pharmacological means. However, epidemiology and clinical research have extensively demonstrated that most individuals who use drugs do not develop dependence. Numerous factors may explain an individual's propensity to addiction. This review discusses these paradigms and summarizes research on individual differences that encompass cultural and sociodemographic factors, psychiatric or psychological vulnerability, and biological or genetic propensity to addiction. Although these different factors often interact in the expression of vulnerable phenotypes, it is possible to alter or control specific sources of vulnerability. For these reasons, integrating individual vulnerability to addiction across different research disciplines is likely to provide the greatest advances for intervention and prevention efforts.
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Affiliation(s)
- Joel Swendsen
- National Center for Scientific Research-CNRS, Université Victor Segalen, Bordeaux, France.
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Cui D, Zhang H, Yang BZ, Listman JB, Li D, Price LH, Carpenter LL, Tyrka AR, Anton RF, Kranzler HR, Gelernter J. Variation in NGFB is associated with primary affective disorders in women. Am J Med Genet B Neuropsychiatr Genet 2011; 156B:401-12. [PMID: 21294249 PMCID: PMC3108453 DOI: 10.1002/ajmg.b.31175] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2010] [Accepted: 01/03/2011] [Indexed: 01/16/2023]
Abstract
Affective disorders (AFDs) are highly comorbid with substance dependence (SD) and both are genetically influenced. However, the specific etiology of the comorbidity is not well understood. We genotyped an array of 1,350 single nucleotide polymorphisms (SNPs) in or near 130 genes in 868 European-Americans (EAs), including 182 individuals with primary AFDs (PAFDs), 214 with SD comorbid with AFD (CAFD), and 472 screened controls. NGFB, which encodes nerve growth factor β and was represented in the array by 15 SNPs, showed the strongest evidence of association, but only among women with PAFDs. Six of the SNPs showed nominally significant association with PAFDs in women (P's = 0.0007-0.01); three (rs2856813, rs4332358, and rs10776799) were empirically significant based on 1,000,000 permutations (P's = 0.008-0.015). Seven haplotypes were significantly associated with PAFDs in women (P's = 0.0014-0.01), of which six were significant based on empirical permutation analysis (minimal P = 0.0045). Four diplotypes were significantly associated with PAFDs in women (global P's = 0.001-0.01). The specific diplotype GG-TC, reconstructed from rs2856813 and rs6678788, showed the strongest evidence of association with PAFDs in women (OR = 4.07, P = 4.2E-05). No SNPs or haplotypes were associated with PAFDs in men or with CAFDs in either sex. We conclude that variation in NGFB is a risk factor for PAFDs in women, but not for CAFD.
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Affiliation(s)
- Donghong Cui
- Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut
- Veterans Affairs Connecticut Healthcare Center, West Haven, Connecticut
| | - Huiping Zhang
- Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut
- Veterans Affairs Connecticut Healthcare Center, West Haven, Connecticut
| | - Bao-Zhu Yang
- Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut
- Veterans Affairs Connecticut Healthcare Center, West Haven, Connecticut
| | - Jennifer B. Listman
- Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut
| | - Dawei Li
- Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut
- Veterans Affairs Connecticut Healthcare Center, West Haven, Connecticut
| | - Lawrence H. Price
- Department of Psychiatry & Human Behavior, Brown University, Providence, Rhode Island
| | - Linda L. Carpenter
- Department of Psychiatry & Human Behavior, Brown University, Providence, Rhode Island
| | - Audrey R. Tyrka
- Department of Psychiatry & Human Behavior, Brown University, Providence, Rhode Island
| | - Raymond F. Anton
- Department of Psychiatry & Behavioral Sciences, Medical University of South Carolina, Charleston, South Carolina
| | - Henry R. Kranzler
- Departments of Psychiatry and Genetics and Developmental Biology, University of Connecticut School of Medicine, Farmington, Connecticut
| | - Joel Gelernter
- Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut
- Department of Genetics, Yale University School of Medicine, New Haven, Connecticut
- Department of Neurobiology, Yale University School of Medicine, New Haven, Connecticut
- Veterans Affairs Connecticut Healthcare Center, West Haven, Connecticut
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Merenäkk L, Mäestu J, Nordquist N, Parik J, Oreland L, Loit HM, Harro J. Effects of the serotonin transporter (5-HTTLPR) and α2A-adrenoceptor (C-1291G) genotypes on substance use in children and adolescents: a longitudinal study. Psychopharmacology (Berl) 2011; 215:13-22. [PMID: 21140256 DOI: 10.1007/s00213-010-2109-z] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2010] [Accepted: 11/19/2010] [Indexed: 10/18/2022]
Abstract
RATIONALE AND OBJECTIVE Twin studies suggest that substance use initiation in children and adolescents is determined primarily by environmental influences, whereas the establishment of use patterns is strongly controlled by genetic factors. The present study analysed the effects of the serotonin transporter promoter polymorphism [5-HT transporter gene-linked polymorphic region (5-HTTLPR)] and the α(2A)-adrenoceptor C-1291G genotype (ADRA2A C-1291G) as well as their interaction effects on alcohol, tobacco and drug use from preadolescence to the late adolescence. METHODS Initial sample of 9-year-old children of Estonian Children Personality Behaviour and Health Study (n = 583) was recalled at ages 15 and 18. Participants reported in all waves how frequently they smoked and used alcohol and illicit drugs. RESULTS 5-HTTLPR had age-dependent effects on alcohol, tobacco and drug use: substance use did not differ by genotype at age 9, but at age 15, the participants with the short (s)/s genotype had higher tobacco use, and at age 18, they were more active alcohol, drug and tobacco users. Effects of ADRA2A C-1291G on drug use were dependent on gender, age and 5-HTTLPR. Males (age 18) with ADRA2A CG genotype, when compared to other participants, tended to have higher drug use especially when they had s/s genotype of 5-HTTLPR. CONCLUSIONS Our results reveal that expression of genetic vulnerability for substance use in children and adolescents may depend on age, gender, interaction of genes, and type of substance.
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Affiliation(s)
- Liis Merenäkk
- Department of Public Health, Estonian Centre of Behavioural and Health Sciences, University of Tartu, Tartu, Estonia
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Potenza MN, Sofuoglu M, Carroll KM, Rounsaville BJ. Neuroscience of behavioral and pharmacological treatments for addictions. Neuron 2011; 69:695-712. [PMID: 21338880 PMCID: PMC3063555 DOI: 10.1016/j.neuron.2011.02.009] [Citation(s) in RCA: 147] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/04/2011] [Indexed: 01/30/2023]
Abstract
Although substantial advances have been made in behavioral and pharmacological treatments for addictions, moving treatment development to the next stage may require novel ways of approaching addictions, particularly ways based on new findings regarding the neurobiological underpinnings of addictions that also assimilate and incorporate relevant information from earlier approaches. In this review, we first briefly review theoretical and biological models of addiction and then describe existing behavioral and pharmacologic therapies for the addictions within this framework. We then propose new directions for treatment development and targets that are informed by recent evidence regarding the heterogeneity of addictions and the neurobiological contributions to these disorders.
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Affiliation(s)
- Marc N Potenza
- Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06519, USA.
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Belin D, Berson N, Balado E, Piazza PV, Deroche-Gamonet V. High-novelty-preference rats are predisposed to compulsive cocaine self-administration. Neuropsychopharmacology 2011; 36:569-79. [PMID: 20980989 PMCID: PMC3055686 DOI: 10.1038/npp.2010.188] [Citation(s) in RCA: 197] [Impact Index Per Article: 14.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Abstract
Sensation/novelty-seeking is amongst the best markers of cocaine addiction in humans. However, its implication in the vulnerability to cocaine addiction is still a matter of debate, as it is unclear whether this trait precedes or follows the development of addiction. Sensation/novelty-seeking trait has been identified in rats on the basis of either novelty-induced locomotor activity (high-responder (HR) trait) or novelty-induced place preference (high-novelty-preference trait (HNP)). HR and HNP traits have been associated with differential sensitivity to psychostimulants. However, it has recently been demonstrated that HR rats do not develop compulsive cocaine self-administration (SA) after protracted exposure to the drug, thereby suggesting that at least one dimension of sensation/novelty seeking in the rat is dissociable from the vulnerability to switch from controlled to compulsive cocaine SA. We therefore investigated whether HNP, as measured as the propensity to choose a new environment in a free choice procedure, as opposed to novelty-induced locomotor activity, predicts the vulnerability to, and the severity of, addiction-like behavior for cocaine. For this, we identified HR/LR rats and HNP/LNP rats before any exposure to cocaine. After 60 days of cocaine SA, each rat was given an addiction score based on three addiction-like behaviors (persistence of responding when the drug is signaled as not available, high breakpoint under progressive ratio schedule and resistance to punishment) that resemble the clinical features of drug addiction, namely inability to refrain from drug seeking, high motivation for the drug and compulsive drug use despite adverse consequences. We show that, as opposed to HR rats, HNP rats represent a sub-population predisposed to compulsive cocaine intake, displaying higher addiction scores than LNP rats. This study thereby provides new insights into the factors predisposing to cocaine addiction, supporting the hypothesis that addiction is sustained by two vulnerable phenotypes: a 'drug use prone' phenotype such as HR which brings an individual to develop drug use and an 'addiction prone' phenotype, such as HNP, which facilitates the shift from sustained to compulsive drug intake and addiction.
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Affiliation(s)
- David Belin
- University of Bordeaux, Bordeaux Cedex, France.
| | - Nadège Berson
- University of Bordeaux, Bordeaux Cedex, France,INSERM U862, Pathophysiology of Addiction, NeuroCentre Magendie, Bordeaux Cedex, France
| | - Eric Balado
- University of Bordeaux, Bordeaux Cedex, France,INSERM U862, Pathophysiology of Addiction, NeuroCentre Magendie, Bordeaux Cedex, France
| | - Pier Vincenzo Piazza
- University of Bordeaux, Bordeaux Cedex, France,INSERM U862, Pathophysiology of Addiction, NeuroCentre Magendie, Bordeaux Cedex, France
| | - Véronique Deroche-Gamonet
- University of Bordeaux, Bordeaux Cedex, France,INSERM U862, Pathophysiology of Addiction, NeuroCentre Magendie, Bordeaux Cedex, France
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Pecoraro A, Woody GE. Medication-assisted treatment for opioid dependence: making a difference in prisons. F1000 MEDICINE REPORTS 2011; 3:1. [PMID: 21399758 PMCID: PMC3042317 DOI: 10.3410/m3-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
This article explores the evolving evidence supporting the provision of opioid maintenance therapies to incarcerated populations.
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Affiliation(s)
- Anna Pecoraro
- Department of Psychiatry, University of Pennsylvania600 Public Ledger Building, 150 South Independence Mall, West, Philadelphia, PA 19106USA
- NIDA Clinical Trials NetworkDelaware Valley Node, Philadelphia, PAUSA
| | - George E. Woody
- Department of Psychiatry, University of Pennsylvania600 Public Ledger Building, 150 South Independence Mall, West, Philadelphia, PA 19106USA
- NIDA Clinical Trials NetworkDelaware Valley Node, Philadelphia, PAUSA
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Nordstrom BR, Gao Y, Glenn AL, Peskin M, Rudo-Hutt AS, Schug RA, Yang Y, Raine A. Neurocriminology. ADVANCES IN GENETICS 2011; 75:255-83. [PMID: 22078483 DOI: 10.1016/b978-0-12-380858-5.00006-x] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
In the past several decades there has been an explosion of research into the biological correlates to antisocial behavior. This chapter reviews the state of current research on the topic, including a review of the genetics, neuroimaging, neuropsychological, and electrophysiological studies in delinquent and antisocial populations. Special attention is paid to the biopsychosocial model and gene-environment interactions in producing antisocial behavior.
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Abstract
Drug addiction is a syndrome of impaired response inhibition and salience attribution, which involves a complex neurocircuitry underlying drug reinforcement, drug craving, and compulsive drug-seeking and drug-taking behaviors despite adverse consequences. The concept of disease stages with transitions from acute rewarding effects to early- and end-stage addiction has had an important impact on the design of nonclinical animal models. This chapter reviews the main advances in nonclinical paradigms that aim to at model (1) positive and negative reinforcing effects of addictive drugs; (2) relapse to drug-seeking behavior; (3) reconsolidation of drug cue memories, and (4) compulsive/impulsive drug intake. In addition, recent small animal neuroimaging studies and invertebrate models will be briefly discussed (see also Bifone and Gozzi, Animal models of ADHD, 2011). Continuous improvement in modeling drug intake, craving, withdrawal symptoms, relapse, and comorbid psychiatric associations is a necessary step to better understand the etiology of the disease and to ultimately foster the discovery, validation and optimization of new efficacious pharmacotherapeutic approaches. The modeling of specific subprocesses or constructs that address clinically defined criteria will ultimately increase our understanding of the disease as a whole. Future research will have to address the questions of whether some of these constructs can be reliably used as outcome measures to assess the effects of a treatment in clinical settings, whether changes in those measures can be a target of therapeutic efforts, and whether they relate to biological markers of traits such as impulsivity, which contribute to increased drug-seeking and may predict binge-like patterns of drug intake.
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Affiliation(s)
- Christian Heidbreder
- Reckitt Benckiser Pharmaceuticals Inc., 10710 Midlothian Turnpike, Suite 430, Richmond, VA, 23235, USA,
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Uys JD, Reissner KJ. Glutamatergic Neuroplasticity in Cocaine Addiction. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2011; 98:367-400. [DOI: 10.1016/b978-0-12-385506-0.00009-0] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
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Genetic repositories for the study of major psychiatric conditions: what do we know about ethnic minorities' genetic vulnerability? Mol Psychiatry 2010; 15:970-5. [PMID: 20177407 DOI: 10.1038/mp.2010.11] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
In spite of considerable efforts, no genes of major effect have been found across an entire diagnostic category in psychiatry. Possible reasons for this may include difficulties in defining the phenotype, the complex relationship between genotype and gene expression and population stratification. This last problem has often been managed by restricting genetic sampling to only one ethnic group. An unintended consequence of using this strategy is that the major repositories of genetic material for the study of psychiatric conditions in the United States suffer from a paucity of genetic samples from non-Caucasian groups. Thus, these groups are being relatively understudied in terms of the genetic antecedents to psychiatric disease. The authors provide solutions including the need to augment the representation of African-American, Latino and Asian-Americans among research participants; a more nuanced approach to identify ancestry; and the development of analytic and genetic strategies to handle the issue of ethnic heterogeneity in samples.
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Abstract
Impulsivity represents a complex, multifaceted construct with relevance to alcohol use, abuse, and dependence. Researchers are refining the definitions and assessment of different subtypes of impulsive behavior and relating these to the causes and consequences of alcohol-related behaviors and disorders. A satellite symposium on alcohol and impulsivity was held at the 2009 convention of the Research Society on Alcoholism. This article provides an overview of the rationale for the symposium, a synopsis of review and original research articles emanating from the symposium, and a description of the implications of the work and possible future research directions.
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Affiliation(s)
- Marc N Potenza
- Departments of Psychiatry and Child Study Center, Yale University School of Medicine, New Haven, Connecticut 06519, USA
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White MA, Grilo CM, O'Malley SS, Potenza MN. Clinical case discussion: binge eating disorder, obesity and tobacco smoking. J Addict Med 2010; 4:11-9. [PMID: 20436923 PMCID: PMC2860740 DOI: 10.1097/adm.0b013e3181ce38c8] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Affiliation(s)
- Marney A. White
- Department of Psychiatry, Yale University School of Medicine
| | - Carlos M. Grilo
- Department of Psychiatry, Yale University School of Medicine
- Department of Psychology, Yale University School of Medicine
| | | | - Marc N. Potenza
- Department of Psychiatry, Yale University School of Medicine
- Child Study Center, Yale University School of Medicine
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