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Zhou X, Li AL, Du WJ, Gao P, Lai B, Fang F, Han Q, Cang J. Genetic Variation A118G in the OPRM1 Gene Underlies the Dimorphic Response to Epidural Opioid-Induced Itch. Neurosci Bull 2025:10.1007/s12264-025-01411-6. [PMID: 40381142 DOI: 10.1007/s12264-025-01411-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2024] [Accepted: 02/21/2025] [Indexed: 05/19/2025] Open
Abstract
Neuraxial opioids, widely used in obstetric and perioperative pain management, often lead to unwanted itch, reducing patient satisfaction. While the μ-opioid receptor has been implicated in opioid-induced itch, the genetic basis for variable itch incidence remains unknown. This study examined 3616 patients receiving epidural opioids, revealing an itch occurrence of 26.55%, with variations among opioid types and gender. Analysis of the OPRM1 gene identified six single-nucleotide polymorphisms, notably rs1799971 (A118G), that correlated with opioid-induced itch. Mouse models with an equivalent A112G mutation showed reduced neuraxial opioid-induced itch and light touch-evoked itch, mirroring human findings. The 118G allele demonstrated an anti-itch effect without impacting analgesia, addiction, or tolerance, offering insights for risk stratification and potential anti-itch pretreatment strategies.
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Affiliation(s)
- Xiaomeng Zhou
- Department of Anesthesia, Department of Pain Medicine, Zhongshan Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontier Center for Brain Science, Institutes of Brain Science, Fudan University, Shanghai, 200032, China
| | - Ai-Lun Li
- Department of Anesthesia, Department of Pain Medicine, Zhongshan Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontier Center for Brain Science, Institutes of Brain Science, Fudan University, Shanghai, 200032, China
| | - Wan-Jie Du
- Department of Anesthesia, Department of Pain Medicine, Zhongshan Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontier Center for Brain Science, Institutes of Brain Science, Fudan University, Shanghai, 200032, China
| | - Pengyu Gao
- Department of Anesthesia, Department of Pain Medicine, Zhongshan Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontier Center for Brain Science, Institutes of Brain Science, Fudan University, Shanghai, 200032, China
| | - Bin Lai
- Department of Anesthesia, Department of Pain Medicine, Zhongshan Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontier Center for Brain Science, Institutes of Brain Science, Fudan University, Shanghai, 200032, China.
| | - Fang Fang
- Department of Anesthesia, Department of Pain Medicine, Zhongshan Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontier Center for Brain Science, Institutes of Brain Science, Fudan University, Shanghai, 200032, China.
| | - Qingjian Han
- Department of Anesthesia, Department of Pain Medicine, Zhongshan Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontier Center for Brain Science, Institutes of Brain Science, Fudan University, Shanghai, 200032, China.
| | - Jing Cang
- Department of Anesthesia, Department of Pain Medicine, Zhongshan Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontier Center for Brain Science, Institutes of Brain Science, Fudan University, Shanghai, 200032, China.
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Løseth G, Eikemo M, Leknes S. Opioid Regulation of Social Homeostasis: Connecting Loneliness to Addiction. Biol Psychiatry 2025; 97:971-981. [PMID: 39608698 DOI: 10.1016/j.biopsych.2024.11.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/04/2024] [Revised: 11/07/2024] [Accepted: 11/18/2024] [Indexed: 11/30/2024]
Abstract
Loneliness heightens the risk of substance use disorder, and a desire to escape this negative feeling motivates drug use. Opioid drugs in particular are believed to target neurobiological circuits involved in social bonding, increasing vulnerability to opioid addiction when social connectedness is lacking. In this narrative review, we consider how current understanding of μ opioid modulation of reward and threat processing across domains sheds light on the mechanisms that link loneliness and substance use. We discuss evidence for state- and context-dependent μ opioid modulation of social affect and behaviors, which appears to promote prioritization of high-value reward options also in the context of threat. Tying this literature to the model of social homeostasis, we argue for a role of μ opioids in regulating social homeostasis across species. Finally, we explore how disruption of social homeostasis in chronic opioid use contributes to continued drug use. We highlight how increasing patients' psychosocial resources and opportunities for social bonding can improve recovery from drug addiction. Throughout, we consider the translational robustness and generalizability of the nonhuman animal evidence in light of existing human research.
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Affiliation(s)
- Guro Løseth
- Department of Psychology, University of Oslo, Oslo, Norway.
| | - Marie Eikemo
- Department of Psychology, University of Oslo, Oslo, Norway; Department of Physics and Computational Radiology, Oslo University Hospital, Oslo, Norway
| | - Siri Leknes
- Department of Psychology, University of Oslo, Oslo, Norway; Department of Physics and Computational Radiology, Oslo University Hospital, Oslo, Norway.
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3
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Borland JM. The effects of different types of social interactions on the electrophysiology of neurons in the nucleus accumbens in rodents. Neurosci Biobehav Rev 2024; 164:105809. [PMID: 39004323 PMCID: PMC11771367 DOI: 10.1016/j.neubiorev.2024.105809] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2024] [Revised: 07/05/2024] [Accepted: 07/08/2024] [Indexed: 07/16/2024]
Abstract
BORLAND, J.M., The effects of different types of social interactions on the electrophysiology of neurons in the nucleus accumbens in rodents, NEUROSCI BIOBEH REV 21(1) XXX-XXX, 2024.-Sociality shapes an organisms' life. The nucleus accumbens is a critical brain region for mental health. In the following review, the effects of different types of social interactions on the physiology of neurons in the nucleus accumbens is synthesized. More specifically, the effects of sex behavior, aggression, social defeat, pair-bonding, play behavior, affiliative interactions, parental behaviors, the isolation from social interactions and maternal separation on measures of excitatory synaptic transmission, intracellular signaling and factors of transcription and translation in neurons in the nucleus accumbens in rodent models are reviewed. Similarities and differences in effects depending on the type of social interaction is then discussed. This review improves the understanding of the molecular and synaptic mechanisms of sociality.
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Potegal M. How it ends: A review of behavioral and psychological phenomena, physiological processes and neural circuits in the termination of aggression in other animals and anger in people. Behav Brain Res 2024; 456:114676. [PMID: 37739229 DOI: 10.1016/j.bbr.2023.114676] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2023] [Revised: 08/26/2023] [Accepted: 09/17/2023] [Indexed: 09/24/2023]
Abstract
More is known about aggression initiation and persistence in other animals, and anger in people, than about their cessation. This review summarizes knowledge of relevant factors in aggression, mostly in vertebrates, and anger termination in people. The latency, probability and intensity of offensive aggression in mice is controlled by activity in a neuronal subpopulation in ventromedial hypothalamus [VMH]. This activity instantiates an aggressive state termed angriffsbereitschaft ["attack-readiness"]. Fighting in many species is broken into bouts with interbout breaks due to fatigue and/or signals from dorsal raphe to VMH. Eventually, losers decide durations and outcomes of fighting by transitioning to submission or flight. Factors reducing angriffsbereitschaft and triggering these defeat behaviors could include metabolic costs, e.g., lactate accumulation and glucose depletion detected by the hypothalamus, central fatigue perhaps sensed by the Salience Network [insula and anterior cingulate gyrus] and pain of injuries, the latter insufficiently blunted by opioid and non-opioid stress analgesia and transduced by anterior VMH neurons. Winners' angriffsbereitschaft continue for awhile, as indicated by post-victory attacks and, perhaps, triumph displays of some species, including humans. In longer term situations, sensory and/or response habituation of aggression may explain the "Dear enemy" tolerance of competitive neighbors. Prolonged satiation of predatory behavior could involve habenula-regulated reduction of dopaminergic reward in nucleus accumbens. Termination of human anger involves at least three processes, metaphorically termed decay, quenching and catharsis. Hypothesized neural mechanisms include anger diminution by negative feedback from accumbens to anterior cingulate and/or activity in the Salience Network that controls anger's "accumulation/offset" phase.
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Affiliation(s)
- M Potegal
- University of Minnesota, United States.
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5
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Nakamoto K, Tokuyama S. Stress-Induced Changes in the Endogenous Opioid System Cause Dysfunction of Pain and Emotion Regulation. Int J Mol Sci 2023; 24:11713. [PMID: 37511469 PMCID: PMC10380691 DOI: 10.3390/ijms241411713] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2023] [Revised: 07/13/2023] [Accepted: 07/13/2023] [Indexed: 07/30/2023] Open
Abstract
Early life stress, such as child abuse and neglect, and psychosocial stress in adulthood are risk factors for psychiatric disorders, including depression and anxiety. Furthermore, exposure to these stresses affects the sensitivity to pain stimuli and is associated with the development of chronic pain. However, the mechanisms underlying the pathogenesis of stress-induced depression, anxiety, and pain control remain unclear. Endogenous opioid signaling is reportedly associated with analgesia, reward, addiction, and the regulation of stress responses and anxiety. Stress alters the expression of various opioid receptors in the central nervous system and sensitivity to opioid receptor agonists and antagonists. μ-opioid receptor-deficient mice exhibit attachment disorders and autism-like behavioral expression patterns, while those with δ-opioid receptor deficiency exhibit anxiety-like behavior. In contrast, deficiency and antagonists of the κ-opioid receptor suppress the stress response. These findings strongly suggest that the expression and dysfunction of the endogenous opioid signaling pathways are involved in the pathogenesis of stress-induced psychiatric disorders and chronic pain. In this review, we summarize the latest basic and clinical research studies on the effects of endogenous opioid signaling on early-life stress, psychosocial stress-induced psychiatric disorders, and chronic pain.
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Affiliation(s)
- Kazuo Nakamoto
- Department of Clinical Pharmacy, School of Pharmaceutical Sciences, Kobe Gakuin University, 1-1-3 Minatojima, Chuo-ku, Kobe 650-8586, Japan
| | - Shogo Tokuyama
- Department of Clinical Pharmacy, School of Pharmaceutical Sciences, Kobe Gakuin University, 1-1-3 Minatojima, Chuo-ku, Kobe 650-8586, Japan
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Cardona-Acosta AM, Bolaños-Guzmán CA. Role of the mesolimbic dopamine pathway in the antidepressant effects of ketamine. Neuropharmacology 2023; 225:109374. [PMID: 36516891 PMCID: PMC9839658 DOI: 10.1016/j.neuropharm.2022.109374] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2022] [Revised: 11/27/2022] [Accepted: 12/07/2022] [Indexed: 12/14/2022]
Abstract
Depression is a complex and highly heterogeneous disorder which diagnosis is based on an exceedingly variable set of clinical symptoms. Current treatments focus almost exclusively on the manipulation of monoamine neurotransmitter systems, but despite considerable efforts, these remain inadequate for a significant proportion of those afflicted by the disorder. The emergence of racemic (R, S)-ketamine as a fast-acting antidepressant has provided an exciting new path for the study of major depressive disorder (MDD) and the search for better therapeutics for its treatment. Previous work suggested that ketamine's mechanism of action is primarily mediated via blockaded of N-methyl-d-aspartate (NMDA) receptors, however, this is an area of active research and clinical and preclinical evidence now indicate that ketamine acts on multiple systems. The last couple of decades have cemented the mesolimbic dopamine reward pathway's involvement in the pathogenesis of MDD and related mood disorders. Exposure to negative stress dysregulates dopamine neuronal activity disrupting reward and motivational processes resulting in anhedonia (lack of pleasure), a hallmark symptom of depression. Although the mechanism(s) underlying ketamine's antidepressant activity continue to be elucidated, current evidence indicate that its therapeutic effects are mediated, at least in part, via long-lasting synaptic changes and subsequent molecular adaptations in brain regions within the mesolimbic dopamine system. Notwithstanding, ketamine is a drug of abuse, and this liability may pose limitations for long term use as an antidepressant. This review outlines the current knowledge of ketamine's actions within the mesolimbic dopamine system and its abuse potential. This article is part of the Special Issue on 'Ketamine and its Metabolites'.
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Affiliation(s)
- Astrid M Cardona-Acosta
- Department of Psychological and Brain Sciences and Program in Neuroscience, Texas A&M University, College Station, TX, 77843, USA
| | - Carlos A Bolaños-Guzmán
- Department of Psychological and Brain Sciences and Program in Neuroscience, Texas A&M University, College Station, TX, 77843, USA.
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7
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Cahill S, Chandola T, Hager R. Genetic Variants Associated With Resilience in Human and Animal Studies. Front Psychiatry 2022; 13:840120. [PMID: 35669264 PMCID: PMC9163442 DOI: 10.3389/fpsyt.2022.840120] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Accepted: 04/19/2022] [Indexed: 11/15/2022] Open
Abstract
Resilience is broadly defined as the ability to maintain or regain functioning in the face of adversity and is influenced by both environmental and genetic factors. The identification of specific genetic factors and their biological pathways underpinning resilient functioning can help in the identification of common key factors, but heterogeneities in the operationalisation of resilience have hampered advances. We conducted a systematic review of genetic variants associated with resilience to enable the identification of general resilience mechanisms. We adopted broad inclusion criteria for the definition of resilience to capture both human and animal model studies, which use a wide range of resilience definitions and measure very different outcomes. Analyzing 158 studies, we found 71 candidate genes associated with resilience. OPRM1 (Opioid receptor mu 1), NPY (neuropeptide Y), CACNA1C (calcium voltage-gated channel subunit alpha1 C), DCC (deleted in colorectal carcinoma), and FKBP5 (FKBP prolyl isomerase 5) had both animal and human variants associated with resilience, supporting the idea of shared biological pathways. Further, for OPRM1, OXTR (oxytocin receptor), CRHR1 (corticotropin-releasing hormone receptor 1), COMT (catechol-O-methyltransferase), BDNF (brain-derived neurotrophic factor), APOE (apolipoprotein E), and SLC6A4 (solute carrier family 6 member 4), the same allele was associated with resilience across divergent resilience definitions, which suggests these genes may therefore provide a starting point for further research examining commonality in resilience pathways.
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Affiliation(s)
- Stephanie Cahill
- Evolution, Infection and Genomics, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, The University of Manchester, Manchester, United Kingdom
- Faculty of Humanities, Cathie Marsh Institute for Social Research, The University of Manchester, Manchester, United Kingdom
| | - Tarani Chandola
- Faculty of Humanities, Cathie Marsh Institute for Social Research, The University of Manchester, Manchester, United Kingdom
- Methods Hub, Department of Sociology, Faculty of Social Sciences, The University of Hong Kong, Hong Kong, Hong Kong SAR, China
| | - Reinmar Hager
- Evolution, Infection and Genomics, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, The University of Manchester, Manchester, United Kingdom
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8
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Calpe-López C, Martínez-Caballero MA, García-Pardo MP, Aguilar MA. Resilience to the effects of social stress on vulnerability to developing drug addiction. World J Psychiatry 2022; 12:24-58. [PMID: 35111578 PMCID: PMC8783163 DOI: 10.5498/wjp.v12.i1.24] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 08/01/2021] [Accepted: 12/23/2021] [Indexed: 02/06/2023] Open
Abstract
We review the still scarce but growing literature on resilience to the effects of social stress on the rewarding properties of drugs of abuse. We define the concept of resilience and how it is applied to the field of drug addiction research. We also describe the internal and external protective factors associated with resilience, such as individual behavioral traits and social support. We then explain the physiological response to stress and how it is modulated by resilience factors. In the subsequent section, we describe the animal models commonly used in the study of resilience to social stress, and we focus on the effects of chronic social defeat (SD), a kind of stress induced by repeated experience of defeat in an agonistic encounter, on different animal behaviors (depression- and anxiety-like behavior, cognitive impairment and addiction-like symptoms). We then summarize the current knowledge on the neurobiological substrates of resilience derived from studies of resilience to the effects of chronic SD stress on depression- and anxiety-related behaviors in rodents. Finally, we focus on the limited studies carried out to explore resilience to the effects of SD stress on the rewarding properties of drugs of abuse, describing the current state of knowledge and suggesting future research directions.
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Affiliation(s)
| | | | - Maria P García-Pardo
- Faculty of Social and Human Sciences, University of Zaragoza, Teruel 44003, Spain
| | - Maria A Aguilar
- Department of Psychobiology, University of Valencia, Valencia 46010, Spain
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Nobile B, Olie E, Ramoz N, Dubois J, Guillaume S, Gorwood P, Courtet P. Association Between the A118G Polymorphism of the OPRM1 Gene and Suicidal Depression in a Large Cohort of Outpatients with Depression. Neuropsychiatr Dis Treat 2021; 17:3109-3118. [PMID: 34703230 PMCID: PMC8525413 DOI: 10.2147/ndt.s324868] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Accepted: 08/19/2021] [Indexed: 12/02/2022] Open
Abstract
BACKGROUND Growing evidences suggest that depression with suicidal ideation (SI) could be a specific phenotype with its own characteristics. Moreover, opioid system deregulation might be implicated in suicidal behaviour (SB). The aim of this study was to determine whether the A118G polymorphism (rs1799971) in ORPM1 (the gene encoding opioid receptor mu 1) is associated with suicidal depression (ie, moderate to severe depression with SI) in a large cohort of outpatients with depression. METHODS GENESE is a large, prospective, naturalistic cohort of French adult outpatients with depression (DSM-IV criteria), treated and followed for 6 weeks. Depression severity was assessed with the Hospital Anxiety and Depression Scale (HADS), and SI with the suicidal item of the Montgomery-Åsberg Depression Rating Scale (MADRS-SI). From this cohort, patients with moderate or severe depression (HADS-D subscale score >11) were selected and classified as without SI (MADRS-SI < 2), or with SI (MADRS-SI ≥ 2). RESULTS The AA/AG genotypes of the A118G polymorphism were significantly associated with suicidal depression in the non-adjusted (OR = 2.32, 95% CI = [1.28; 4.18]; p-value = 0.005) and in the adjusted models (OR = 2.54, 95% CI = [1.35; 4.78]; p-value = 0.004). CONCLUSION Outpatients with depression harbouring the A allele are at higher risk of SI (and possibly SB) than those carrying the G allele. More studies are needed to better understand the link between this polymorphism and SB.
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Affiliation(s)
- Benedicte Nobile
- Department of Emergency Psychiatry and Acute Care, CHU Montpellier, Montpellier, France
- IGF, University of Montpellier, CNRS, INSERM, Montpellier, France
| | - Emilie Olie
- Department of Emergency Psychiatry and Acute Care, CHU Montpellier, Montpellier, France
- IGF, University of Montpellier, CNRS, INSERM, Montpellier, France
- FondaMental Foundation, Créteil, France
| | - Nicolas Ramoz
- Inserm UMRS1266, Institute of Psychiatry and Neuroscience of Paris, Paris, France
| | - Jonathan Dubois
- Department of Emergency Psychiatry and Acute Care, CHU Montpellier, Montpellier, France
- IGF, University of Montpellier, CNRS, INSERM, Montpellier, France
| | - Sebastien Guillaume
- Department of Emergency Psychiatry and Acute Care, CHU Montpellier, Montpellier, France
- IGF, University of Montpellier, CNRS, INSERM, Montpellier, France
- FondaMental Foundation, Créteil, France
| | - Philip Gorwood
- Inserm UMRS1266, Institute of Psychiatry and Neuroscience of Paris, Paris, France
| | - Philippe Courtet
- Department of Emergency Psychiatry and Acute Care, CHU Montpellier, Montpellier, France
- IGF, University of Montpellier, CNRS, INSERM, Montpellier, France
- FondaMental Foundation, Créteil, France
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10
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LeClair KB, Chan KL, Kaster MP, Parise LF, Burnett CJ, Russo SJ. Individual history of winning and hierarchy landscape influence stress susceptibility in mice. eLife 2021; 10:71401. [PMID: 34581271 PMCID: PMC8497051 DOI: 10.7554/elife.71401] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Accepted: 09/27/2021] [Indexed: 12/11/2022] Open
Abstract
Social hierarchy formation is strongly evolutionarily conserved. Across species, rank within social hierarchy has large effects on health and behavior. To investigate the relationship between social rank and stress susceptibility, we exposed ranked male and female mice to social and non-social stressors and manipulated social hierarchy position. We found that rank predicts same sex social stress outcomes: dominance in males and females confers resilience while subordination confers susceptibility. Pre-existing rank does not predict non-social stress outcomes in females and weakly does so in males, but rank emerging under stress conditions reveals social interaction deficits in male and female subordinates. Both history of winning and rank of cage mates affect stress susceptibility in males: rising to the top rank through high mobility confers resilience and mice that lose dominance lose stress resilience, although gaining dominance over a subordinate animal does not confer resilience. Overall, we have demonstrated a relationship between social status and stress susceptibility, particularly when taking into account individual history of winning and the overall hierarchy landscape in male and female mice.
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Affiliation(s)
- Katherine B LeClair
- Nash Family Department of Neuroscience, New York, United States.,Friedman Brain Institute, New York, United States.,Graduate School of Biological Science, Icahn School of Medicine at Mount Sinai, New York, United States
| | - Kenny L Chan
- Nash Family Department of Neuroscience, New York, United States.,Friedman Brain Institute, New York, United States
| | - Manuella P Kaster
- Nash Family Department of Neuroscience, New York, United States.,Friedman Brain Institute, New York, United States.,Department of Biochemistry, Federal University of Santa Catarina, Santa Catarina, Brazil
| | - Lyonna F Parise
- Nash Family Department of Neuroscience, New York, United States.,Friedman Brain Institute, New York, United States
| | - Charles Joseph Burnett
- Nash Family Department of Neuroscience, New York, United States.,Friedman Brain Institute, New York, United States
| | - Scott J Russo
- Nash Family Department of Neuroscience, New York, United States.,Friedman Brain Institute, New York, United States.,Graduate School of Biological Science, Icahn School of Medicine at Mount Sinai, New York, United States
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11
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Toddes C, Lefevre EM, Brandner DD, Zugschwert L, Rothwell PE. μ-Opioid Receptor (Oprm1) Copy Number Influences Nucleus Accumbens Microcircuitry and Reciprocal Social Behaviors. J Neurosci 2021; 41:7965-7977. [PMID: 34301826 PMCID: PMC8460143 DOI: 10.1523/jneurosci.2440-20.2021] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2020] [Revised: 02/17/2021] [Accepted: 06/21/2021] [Indexed: 11/21/2022] Open
Abstract
The μ-opioid receptor regulates reward derived from both drug use and natural experiences, including social interaction, through actions in the nucleus accumbens. Here, we studied nucleus accumbens microcircuitry and social behavior in male and female mice with heterozygous genetic knockout of the μ-opioid receptor (Oprm1+/-). This genetic condition models the partial reduction of μ-opioid receptor signaling reported in several neuropsychiatric disorders. We first analyzed inhibitory synapses in the nucleus accumbens, using methods that differentiate between medium spiny neurons (MSNs) expressing the D1 or D2 dopamine receptor. Inhibitory synaptic transmission was increased in D2-MSNs of male mutants, but not female mutants, while the expression of gephyrin mRNA and the density of inhibitory synaptic puncta at the cell body of D2-MSNs was increased in mutants of both sexes. Some of these changes were more robust in Oprm1+/- mutants than Oprm1-/- mutants, demonstrating that partial reductions of μ-opioid signaling can have large effects. At the behavioral level, social conditioned place preference and reciprocal social interaction were diminished in Oprm1+/- and Oprm1-/- mutants of both sexes. Interaction with Oprm1 mutants also altered the social behavior of wild-type test partners. We corroborated this latter result using a social preference task, in which wild-type mice preferred interactions with another typical mouse over Oprm1 mutants. Surprisingly, Oprm1-/- mice preferred interactions with other Oprm1-/- mutants, although these interactions did not produce a conditioned place preference. Our results support a role for partial dysregulation of μ-opioid signaling in social deficits associated with neuropsychiatric conditions.SIGNIFICANCE STATEMENT Activation of the μ-opioid receptor plays a key role in the expression of normal social behaviors. In this study, we examined brain function and social behavior of female and male mice, with either partial or complete genetic deletion of μ-opioid receptor expression. We observed abnormal social behavior following both genetic manipulations, as well as changes in the structure and function of synaptic input to a specific population of neurons in the nucleus accumbens, which is an important brain region for social behavior. Synaptic changes were most robust when μ-opioid receptor expression was only partially lost, indicating that small reductions in μ-opioid receptor signaling can have a large impact on brain function and behavior.
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Affiliation(s)
- Carlee Toddes
- Graduate Program in Neuroscience, University of Minnesota, Minneapolis, Minnesota 55455
| | - Emilia M Lefevre
- Department of Neuroscience, University of Minnesota, Minneapolis, Minnesota 55455
| | - Dieter D Brandner
- Graduate Program in Neuroscience, University of Minnesota, Minneapolis, Minnesota 55455
- Medical Scientist Training Program, University of Minnesota, Minneapolis, Minnesota 55455
| | - Lauryn Zugschwert
- Neuroscience Program and Department of Biology, University of St. Thomas, St. Paul, Minnesota 55105
| | - Patrick E Rothwell
- Department of Neuroscience, University of Minnesota, Minneapolis, Minnesota 55455
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12
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Daniel AM, Rushing BG, Tapia Menchaca KY. Variation of the human mu-opioid receptor (OPRM1) gene predicts vulnerability to frustration. Sci Rep 2020; 10:21840. [PMID: 33318511 PMCID: PMC7736895 DOI: 10.1038/s41598-020-78783-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2020] [Accepted: 11/19/2020] [Indexed: 11/09/2022] Open
Abstract
Understanding the emotional reaction to loss, or frustration, is a critical problem for the field of mental health. Animal models of loss have pointed to the opioid system as a nexus of frustration, physical pain, and substance abuse. However, few attempts have been made to connect the results of animal models of loss to human behavior. Allelic differences in the human mu opioid receptor gene, notably the A118G single nucleotide polymorphism, have been linked to individual differences in pain sensitivity, depressive symptoms, and reward processing. The present study explored the relationship between A118G and behavior in two frustrating tasks in humans. Results showed that carriers of the mutant G-allele were slower to recover behavior following a reward downshift and abandoned a frustrating task earlier than those without the mutation. Additionally, G-carriers were more sensitive to physical pain. These results highlight the overlap between frustration and pain, and suggest that genetic variation in opioid tone may contribute to individual differences in vulnerability and resilience following emotional disturbances.
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Affiliation(s)
- Alan M Daniel
- Department of Science and Math, Texas A&M University-San Antonio, One University Way, San Antonio, TX, 78224, USA.
| | - Brenda G Rushing
- Department of Science and Math, Texas A&M University-San Antonio, One University Way, San Antonio, TX, 78224, USA
| | - Karla Y Tapia Menchaca
- Department of Science and Math, Texas A&M University-San Antonio, One University Way, San Antonio, TX, 78224, USA
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Sial OK, Parise EM, Parise LF, Gnecco T, Bolaños-Guzmán CA. Ketamine: The final frontier or another depressing end? Behav Brain Res 2020; 383:112508. [PMID: 32017978 PMCID: PMC7127859 DOI: 10.1016/j.bbr.2020.112508] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2019] [Revised: 01/15/2020] [Accepted: 01/23/2020] [Indexed: 12/12/2022]
Abstract
Two decades ago, the observation of a rapid and sustained antidepressant response after ketamine administration provided an exciting new avenue in the search for more effective therapeutics for the treatment of clinical depression. Research elucidating the mechanism(s) underlying ketamine's antidepressant properties has led to the development of several hypotheses, including that of disinhibition of excitatory glutamate neurons via blockade of N-methyl-d-aspartate (NMDA) receptors. Although the prominent understanding has been that ketamine's mode of action is mediated solely via the NMDA receptor, this view has been challenged by reports implicating other glutamate receptors such as AMPA, and other neurotransmitter systems such as serotonin and opioids in the antidepressant response. The recent approval of esketamine (Spravato™) for the treatment of depression has sparked a resurgence of interest for a deeper understanding of the mechanism(s) underlying ketamine's actions and safe therapeutic use. This review aims to present our current knowledge on both NMDA and non-NMDA mechanisms implicated in ketamine's response, and addresses the controversy surrounding the antidepressant role and potency of its stereoisomers and metabolites. There is much that remains to be known about our understanding of ketamine's antidepressant properties; and although the arrival of esketamine has been received with great enthusiasm, it is now more important than ever that its mechanisms of action be fully delineated, and both the short- and long-term neurobiological/functional consequences of its treatment be thoroughly characterized.
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MESH Headings
- Antidepressive Agents/pharmacology
- Antidepressive Agents/therapeutic use
- Depressive Disorder, Major/drug therapy
- Depressive Disorder, Treatment-Resistant/drug therapy
- Dopamine Plasma Membrane Transport Proteins/drug effects
- Excitatory Amino Acid Antagonists/pharmacology
- Excitatory Amino Acid Antagonists/therapeutic use
- Humans
- Ketamine/pharmacology
- Ketamine/therapeutic use
- Norepinephrine Plasma Membrane Transport Proteins/drug effects
- Receptor, Muscarinic M1/drug effects
- Receptors, AMPA/drug effects
- Receptors, Dopamine D2/drug effects
- Receptors, N-Methyl-D-Aspartate/drug effects
- Receptors, Opioid, delta/drug effects
- Receptors, Opioid, kappa/drug effects
- Receptors, Opioid, mu/drug effects
- Receptors, Serotonin, 5-HT3/drug effects
- Receptors, sigma/drug effects
- Serotonin Plasma Membrane Transport Proteins/drug effects
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Affiliation(s)
- Omar K Sial
- Texas A&M University: Department of Psychological and Brain Sciences, 4325 TAMU, College Station, TX, 77843, USA
| | - Eric M Parise
- Fishberg Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, 1 Gustave L. Levy Place, New York, NY, 10029, USA
| | - Lyonna F Parise
- Fishberg Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, 1 Gustave L. Levy Place, New York, NY, 10029, USA
| | - Tamara Gnecco
- Texas A&M University: Department of Psychological and Brain Sciences, 4325 TAMU, College Station, TX, 77843, USA
| | - Carlos A Bolaños-Guzmán
- Texas A&M University: Department of Psychological and Brain Sciences, 4325 TAMU, College Station, TX, 77843, USA.
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14
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Affiliation(s)
- Marlene A Wilson
- Department of Pharmacology, Physiology and Neuroscience, University of South Carolina School of Medicine, Columbia, SC, United States
- Columbia VA Health Care System, Columbia, SC, United States
| | - Alexander J McDonald
- Department of Pharmacology, Physiology and Neuroscience, University of South Carolina School of Medicine, Columbia, SC, United States
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15
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Buchholz VN, Mühle C, Kornhuber J, Lenz B. Lower Digit Ratio (2D:4D) Indicative of Excess Prenatal Androgen Is Associated With Increased Sociability and Greater Social Capital. Front Behav Neurosci 2019; 13:246. [PMID: 31866841 PMCID: PMC6906175 DOI: 10.3389/fnbeh.2019.00246] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2019] [Accepted: 10/07/2019] [Indexed: 02/02/2023] Open
Abstract
Positive social interactions are crucial for human well-being. Elevated prenatal exposure to testosterone as indicated by a low second-to-fourth finger length ratio (2D:4D) relates to more aggressive/hostile behavior in men of low 2D:4D, especially in challenging situations. How much people enjoy interacting with others is determined by the personality trait sociability. Given its role in approach and avoidance behavior, sociability might also be influenced by prenatal sex hormones, but studies are inconclusive so far. Here, we investigated the association between 2D:4D and the personality trait sociability complemented by personal social capital and personal social network size, in a population-based cohort of 4998 men. Lower 2D:4D correlated significantly with higher trait sociability, bigger personal social capital, and larger personal social network size. These effects were consistent across both hands separately and their mean value. Furthermore, both factors of sociability (1) liking party and company of friends and (2) isolation intolerance, correlated significantly with the prenatal testosterone marker. The exploratory analysis revealed no link between 2D:4D and responses to the personality trait aggression items or items of anti-social-personality disorder. Our data suggest that prenatal androgen exposure organizes the brain with lasting effects on social behavior.
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Affiliation(s)
- Verena N Buchholz
- Addiction Medicine, Lausanne University Hospital CHUV, University of Lausanne, Lausanne, Switzerland; Addiction Switzerland, Lausanne, Switzerland; Centre for Addiction and Mental Health, Toronto, ON, Canada; University of the West of England, Frenchay Campus, Bristol, United Kingdom . La Source, School of Nursing Sciences, HES-SO University of Applied Sciences and Arts of Western Switzerland, Lausanne, Switzerland . Institut für Epidemiologie, Biostatistik und Prävention, Hirschengraben, Zurich, Switzerland . Addiction Medicine, Lausanne University Hospital CHUV, University of Lausanne, Lausanne, Switzerland . Addiction Medicine, Lausanne University Hospital CHUV, University of Lausanne, Lausanne, Switzerland
- Department of Psychiatry and Psychotherapy, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Erlangen, Germany
| | - Christiane Mühle
- Addiction Medicine, Lausanne University Hospital CHUV, University of Lausanne, Lausanne, Switzerland; Addiction Switzerland, Lausanne, Switzerland; Centre for Addiction and Mental Health, Toronto, ON, Canada; University of the West of England, Frenchay Campus, Bristol, United Kingdom . La Source, School of Nursing Sciences, HES-SO University of Applied Sciences and Arts of Western Switzerland, Lausanne, Switzerland . Institut für Epidemiologie, Biostatistik und Prävention, Hirschengraben, Zurich, Switzerland . Addiction Medicine, Lausanne University Hospital CHUV, University of Lausanne, Lausanne, Switzerland . Addiction Medicine, Lausanne University Hospital CHUV, University of Lausanne, Lausanne, Switzerland
- Department of Psychiatry and Psychotherapy, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Erlangen, Germany
| | - Johannes Kornhuber
- Addiction Medicine, Lausanne University Hospital CHUV, University of Lausanne, Lausanne, Switzerland; Addiction Switzerland, Lausanne, Switzerland; Centre for Addiction and Mental Health, Toronto, ON, Canada; University of the West of England, Frenchay Campus, Bristol, United Kingdom . La Source, School of Nursing Sciences, HES-SO University of Applied Sciences and Arts of Western Switzerland, Lausanne, Switzerland . Institut für Epidemiologie, Biostatistik und Prävention, Hirschengraben, Zurich, Switzerland . Addiction Medicine, Lausanne University Hospital CHUV, University of Lausanne, Lausanne, Switzerland . Addiction Medicine, Lausanne University Hospital CHUV, University of Lausanne, Lausanne, Switzerland
- Department of Psychiatry and Psychotherapy, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Erlangen, Germany
| | - Bernd Lenz
- Addiction Medicine, Lausanne University Hospital CHUV, University of Lausanne, Lausanne, Switzerland; Addiction Switzerland, Lausanne, Switzerland; Centre for Addiction and Mental Health, Toronto, ON, Canada; University of the West of England, Frenchay Campus, Bristol, United Kingdom . La Source, School of Nursing Sciences, HES-SO University of Applied Sciences and Arts of Western Switzerland, Lausanne, Switzerland . Institut für Epidemiologie, Biostatistik und Prävention, Hirschengraben, Zurich, Switzerland . Addiction Medicine, Lausanne University Hospital CHUV, University of Lausanne, Lausanne, Switzerland . Addiction Medicine, Lausanne University Hospital CHUV, University of Lausanne, Lausanne, Switzerland
- Department of Psychiatry and Psychotherapy, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Erlangen, Germany
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16
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Attenuation of antidepressant and antisuicidal effects of ketamine by opioid receptor antagonism. Mol Psychiatry 2019; 24:1779-1786. [PMID: 31467392 DOI: 10.1038/s41380-019-0503-4] [Citation(s) in RCA: 96] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2018] [Revised: 04/30/2019] [Accepted: 05/17/2019] [Indexed: 12/12/2022]
Abstract
We recently reported that naltrexone blocks antidepressant effects of ketamine in humans, indicating that antidepressant effects of ketamine require opioid receptor activation. However, it is unknown if opioid receptors are also involved in ketamine's antisuicidality effects. Here, in a secondary analysis of our recent clinical trial, we test whether naltrexone attenuates antisuicidality effects of ketamine. Participants were pretreated with naltrexone or placebo prior to intravenous ketamine in a double-blinded crossover design. Suicidality was measured with the Hamilton Depression Rating Scale item 3, Montgomery-Åsberg Depression Rating Scale item 10, and Columbia Suicide Severity Rating Scale. In the 12 participants who completed naltrexone and placebo conditions, naltrexone attenuated the antisuicidality effects of ketamine on all three suicidality scales/subscales (linear mixed model, fixed pretreatment effect, p < 0.01). Results indicate that opioid receptor activation plays a significant role in the antisuicidality effects of ketamine.
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Abstract
Drug addiction is a worldwide societal problem and public health burden, and results from recreational drug use that develops into a complex brain disorder. The opioid system, one of the first discovered neuropeptide systems in the history of neuroscience, is central to addiction. Recently, opioid receptors have been propelled back on stage by the rising opioid epidemics, revolutions in G protein-coupled receptor research and fascinating developments in basic neuroscience. This Review discusses rapidly advancing research into the role of opioid receptors in addiction, and addresses the key questions of whether we can kill pain without addiction using mu-opioid-receptor-targeting opiates, how mu- and kappa-opioid receptors operate within the neurocircuitry of addiction and whether we can bridge human and animal opioid research in the field of drug abuse.
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Affiliation(s)
- Emmanuel Darcq
- Douglas Mental Health Institute, Department of Psychiatry, McGill University, Montreal, Quebec, Canada
| | - Brigitte Lina Kieffer
- Douglas Mental Health Institute, Department of Psychiatry, McGill University, Montreal, Quebec, Canada. .,Institut de Génétique et de Biologie Moléculaire et Cellulaire, INSERM, Centre National de la Recherche Scientifique and University of Strasbourg, Strasbourg, France.
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18
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Alfimova MV, Korovaitseva GI, Kondratyev NV, Smirnova SV, Lezheiko TV, Golimbet VE. Assessment of Effects of the OPRD1 and OPRM1 Genes Encoding Opioid Receptors on Apathy in Schizophrenia. RUSS J GENET+ 2019. [DOI: 10.1134/s1022795419070020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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19
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Synaptic Regulation by OPRM1 Variants in Reward Neurocircuitry. J Neurosci 2019; 39:5685-5696. [PMID: 31109961 DOI: 10.1523/jneurosci.2317-18.2019] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2018] [Revised: 05/03/2019] [Accepted: 05/03/2019] [Indexed: 12/12/2022] Open
Abstract
Mu-opioid receptors (MORs) are the primary site of action of opioid drugs, both licit and illicit. Susceptibility to opioid addiction is associated with variants in the gene encoding the MOR, OPRM1 Varying with ethnicity, ∼25% of humans carry a single nucleotide polymorphism (SNP) in OPRM1 (A118G). This SNP produces a nonsynonymous amino acid substitution, replacing asparagine (N40) with aspartate (D40), and has been linked with an increased risk for drug addiction. While a murine model of human OPRM1 A118G (A112G in mouse) recapitulates most of the phenotypes reported in humans, the neuronal mechanisms underlying these phenotypes remain elusive. Here, we investigated the impact of A118G on opioid regulation of synaptic transmission in mesolimbic VTA dopaminergic neurons. Using electrophysiology, we showed that both inhibitory and excitatory inputs to VTA dopaminergic neurons projecting to the NAc medial shell were suppressed by the MOR agonists DAMGO and morphine, which caused a shift in the excitatory/inhibitory balance and an increased action potential firing rate. Mice carrying the 112G/G allele exhibited lower sensitivity to DAMGO and morphine compared with major allele carriers (112A/A). Paradoxically, DAMGO produced facilitatory effects on mEPSCs, which were mediated by presynaptic GABAB receptors. However, this was only prominent in homozygous major allele carriers, which could explain a stronger shift in action potential firing in 112A/A mice. This study provides a better understanding on the neurobiological mechanisms that may underlie risk of addiction development in carriers of the A118G SNP in OPRM1 SIGNIFICANCE STATEMENT The pandemic of opioid drug abuse is associated with many socioeconomic burdens. The primary brain target of opioid drugs is the μ-opioid receptor (MOR), encoded by the OPRM1 gene, which is highly polymorphic in humans. Using a mouse model of the human OPRM1 A118G single nucleotide polymorphism (SNP) (A112G in mice), we demonstrated that MOR and GABAB signaling coordinate in regulating mesolimbic dopamine neuronal firing via presynaptic regulation. The A118G SNP affects MOR-mediated suppression of GABA and glutamate release, showing weaker efficacy of synaptic regulation by MORs. These results may shed light on whether MOR SNPs need to be considered for devising effective therapeutic interventions.
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20
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Weidler C, Wagels L, Regenbogen C, Hofhansel L, Blendy JA, Clemens B, Montag C, Habel U. The influence of the OPRM1 (A118G) polymorphism on behavioral and neural correlates of aggression in healthy males. Neuropharmacology 2018; 156:107467. [PMID: 30552906 DOI: 10.1016/j.neuropharm.2018.12.014] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2018] [Revised: 11/26/2018] [Accepted: 12/11/2018] [Indexed: 02/06/2023]
Abstract
Current models of aggression suggest that in addition to personality traits and environmental factors, biological vulnerability associated with genetics substantially impacts aggressive behavior. In a functional imaging study, we investigated the influence of the single nucleotide polymorphism of the mu 1 subtype opioid receptor gene (OPRM1), implicated in sociability, on correlates of trait and state aggression to delineate the function of these influences in aggression. A key aim was further to differentiate different aspects of aggressive reactions - namely, the reaction to provocation and the decision to punish an opponent. 59 healthy males performed a modified Taylor Aggression Paradigm during functional magnetic resonance imaging. The implementation of the paradigm allowed for individual assessments of the decision to behave aggressively, the experience of provocation and the ramification of punishment for the participant or the opponent. The influence of variation in the OPRM1 gene was measured by the functional A118G polymorphism. G allele carriers showed lower levels of general aggression and self-reported physical aggression. Additionally, these participants exhibited increased activation in dorsolateral prefrontal, orbitofrontal, anterior cingulate and insular cortices when choosing higher punishments for the opponent. The OPRM1 polymorphism did not influence aggression in reaction to social provocation. Thus, we suggest that this genetic variant affects one's trait aggressiveness rather than actual behavioral reactivity to provocation. Investigating brain regions that are specifically linked to provocation yielded activation in cortico-limbic circuits which might mediate the evaluation of provocation and the experience of anger and thus shed light on neural processes underlying the risk for aggressive behavior. This article is part of the Special Issue entitled 'Current status of the neurobiology of aggression and impulsivity'.
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Affiliation(s)
- Carmen Weidler
- Department of Psychiatry, Psychotherapy and Psychosomatics, Faculty of Medicine, RWTH Aachen University, 52074, Aachen, Germany.
| | - Lisa Wagels
- Department of Psychiatry, Psychotherapy and Psychosomatics, Faculty of Medicine, RWTH Aachen University, 52074, Aachen, Germany; JARA Institute Brain Structure Function Relationship Institute for Neuroscience and Medicine (INM 10), Forschungszentrum Jülich, 52425 Jülich, Germany
| | - Christina Regenbogen
- Department of Psychiatry, Psychotherapy and Psychosomatics, Faculty of Medicine, RWTH Aachen University, 52074, Aachen, Germany; Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden
| | - Lena Hofhansel
- Department of Psychiatry, Psychotherapy and Psychosomatics, Faculty of Medicine, RWTH Aachen University, 52074, Aachen, Germany; JARA Institute Brain Structure Function Relationship Institute for Neuroscience and Medicine (INM 10), Forschungszentrum Jülich, 52425 Jülich, Germany
| | - Julie A Blendy
- Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Benjamin Clemens
- Department of Psychiatry, Psychotherapy and Psychosomatics, Faculty of Medicine, RWTH Aachen University, 52074, Aachen, Germany
| | - Christian Montag
- Institute of Psychology and Education, Ulm University, Ulm, Germany; The Clinical Hospital of Chengdu Brain Science Institute, MOE Key Lab for Neuroinformation, University of Electronic Science and Technology of Chinöa, Chengdu, China
| | - Ute Habel
- Department of Psychiatry, Psychotherapy and Psychosomatics, Faculty of Medicine, RWTH Aachen University, 52074, Aachen, Germany; JARA Institute Brain Structure Function Relationship Institute for Neuroscience and Medicine (INM 10), Forschungszentrum Jülich, 52425 Jülich, Germany
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21
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Lutz PE, Gross JA, Dhir SK, Maussion G, Yang J, Bramoulle A, Meaney MJ, Turecki G. Epigenetic Regulation of the Kappa Opioid Receptor by Child Abuse. Biol Psychiatry 2018; 84:751-761. [PMID: 28886759 DOI: 10.1016/j.biopsych.2017.07.012] [Citation(s) in RCA: 55] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2016] [Revised: 06/14/2017] [Accepted: 07/14/2017] [Indexed: 12/11/2022]
Abstract
BACKGROUND Experiences of abuse and neglect during childhood are major predictors of the emergence of depressive and suicidal behaviors throughout life. The underlying biological mechanisms, however, remain poorly understood. Here, we focused on the opioid system as a potential brain substrate mediating these effects. METHODS Postmortem samples from three brain structures regulating social bonds and emotions were analyzed. Groups were constituted of depressed individuals who died by suicide, with or without a history of severe child abuse, and of psychiatrically healthy control subjects. Expression of opioid peptides and receptors was measured using real-time polymerase chain reaction. DNA methylation, a major epigenetic mark, was investigated using targeted bisulfite sequencing and characterized at functional level using in vitro reporter assays. Finally, oxidative bisulfite sequencing was used to differentiate methylation and hydroxymethylation of DNA. RESULTS A history of child abuse specifically associated in the anterior insula with a downregulation of the kappa opioid receptor (Kappa), as well as decreased DNA methylation in the second intron of the Kappa gene. In vitro assays further showed that this intron functions as a genomic enhancer where glucocorticoid receptor binding regulates Kappa expression, unraveling a new mechanism mediating the well-established interactions between endogenous opioids and stress. Finally, results showed that child abuse is associated in the Kappa intron with a selective reduction in levels of DNA hydroxymethylation, likely mediating the observed downregulation of the receptor. CONCLUSIONS Altogether, our findings uncover new facets of Kappa physiology, whereby this receptor may be epigenetically regulated by stressful experiences, in particular as a function of early social life.
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Affiliation(s)
- Pierre-Eric Lutz
- McGill Group for Suicide Studies, Douglas Mental Health University Institute, McGill University, Verdun, Quebec, Canada. H4H 1R3
| | - Jeffrey A Gross
- McGill Group for Suicide Studies, Douglas Mental Health University Institute, McGill University, Verdun, Quebec, Canada. H4H 1R3
| | - Sabine K Dhir
- Douglas Mental Health University Institute, McGill University, Verdun, Quebec, Canada. H4H 1R3
| | - Gilles Maussion
- McGill Group for Suicide Studies, Douglas Mental Health University Institute, McGill University, Verdun, Quebec, Canada. H4H 1R3
| | - Jennie Yang
- McGill Group for Suicide Studies, Douglas Mental Health University Institute, McGill University, Verdun, Quebec, Canada. H4H 1R3
| | - Alexandre Bramoulle
- McGill Group for Suicide Studies, Douglas Mental Health University Institute, McGill University, Verdun, Quebec, Canada. H4H 1R3
| | - Michael J Meaney
- Douglas Mental Health University Institute, McGill University, Verdun, Quebec, Canada. H4H 1R3
| | - Gustavo Turecki
- McGill Group for Suicide Studies, Douglas Mental Health University Institute, McGill University, Verdun, Quebec, Canada. H4H 1R3.
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22
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Partington LC, Borelli JL, Smiley P, Jarvik E, Rasmussen HF, Seaman LC, Nurmi EL. Parental overcontrol x OPRM1 genotype interaction predicts school-aged children's sympathetic nervous system activation in response to performance challenge. RESEARCH IN DEVELOPMENTAL DISABILITIES 2018; 82:39-52. [PMID: 29706406 DOI: 10.1016/j.ridd.2018.04.011] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/31/2017] [Revised: 04/14/2018] [Accepted: 04/15/2018] [Indexed: 06/08/2023]
Abstract
Parental overcontrol (OC), the excessive regulation of a child's behavior, cognition, and emotion, is associated with the development of child anxiety. While studies have shown that genetic factors may increase sensitivity to stress, genetic vulnerability to parental OC has not been examined in anxiety etiology. A functional polymorphism in the mu opioid receptor OPRM1 (A118G, rs1799971) has been shown to impact stress reactivity. Using a community sample of children (N = 85, 9-12 years old), we examined the main and interactive effects of maternal OC and child OPRM1 genotype in predicting children's sympathetic nervous system reactivity during a performance stressor. Neither OC nor genotype predicted children's electrodermal activity (EDA); however, the interaction between OC and child genotype significantly predicted stress reactivity, as indexed by EDA, during the challenging task. Among children with the minor G-allele, higher maternal OC was associated with higher reactivity. In A homozygotes, maternal OC was not associated with EDA, suggesting a diathesis-stress pattern of gene x environment interaction. We discuss implications for anxiety etiology and intervention.
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Affiliation(s)
| | | | | | | | | | | | - Erika L Nurmi
- University of California, Los Angeles, United States
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23
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Boparai S, Borelli JL, Partington L, Smiley P, Jarvik E, Rasmussen HF, Seaman LC, Nurmi EL. Interaction between the Opioid Receptor OPRM1 Gene and Mother-Child Language Style Matching Prospectively Predicts Children's Separation Anxiety Disorder Symptoms. RESEARCH IN DEVELOPMENTAL DISABILITIES 2018; 82:120-131. [PMID: 29576267 DOI: 10.1016/j.ridd.2018.03.002] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/16/2017] [Revised: 02/24/2018] [Accepted: 03/03/2018] [Indexed: 06/08/2023]
Abstract
Recent research suggests that lower mother-child language style matching (LSM) is associated with greater physiological reactivity and insecure attachment in school-aged children, but to date no studies have explored this measure of parent-child behavioral matching for its association with children's anxiety symptoms, a well-known correlate of attachment insecurity and heightened physiological reactivity. There is also considerable evidence of genetic risk for anxiety, including possession of the OPRM1 minor allele, 118G. In the current study (N = 44), we expand upon what is known about children's genetic and environmental risk for anxiety by examining the unique and interactive effects of mother-child LSM and the OPRM1 polymorphism A118G on school-aged children's separation anxiety disorder (SAD) symptoms. SAD symptoms were measured both concurrently with LSM and OPRM1 genotype and two years later through self-report. No significant associations emerged between LSM or OPRM1 and concurrent Time 1 SAD symptoms. However, lower LSM and 118G minor allele possession were both associated with greater SAD symptoms at Time 2; further, the interaction between LSM and OPRM1 genotype significantly predicted SAD symptoms beyond the main effects of the two variables. Possession of the minor allele was only associated with greater SAD symptoms among children in low LSM dyads, whereas children with the minor allele in high LSM dyads showed non-significantly lower SAD symptoms. These findings and a proportion affected analysis provide support for a differential susceptibility model of gene by environment interactions for the OPRM1 gene. We discuss the implications for predicting children's separation anxiety across development.
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Affiliation(s)
| | | | | | | | | | | | | | - Erika L Nurmi
- University of California, Los Angeles, United States
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24
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Lutz P, Courtet P, Calati R. The opioid system and the social brain: implications for depression and suicide. J Neurosci Res 2018; 98:588-600. [DOI: 10.1002/jnr.24269] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2018] [Revised: 05/25/2018] [Accepted: 05/29/2018] [Indexed: 12/11/2022]
Affiliation(s)
- Pierre‐Eric Lutz
- Centre National de la Recherche Scientifique, Université de Strasbourg, Institut des Neurosciences Cellulaires et Intégratives, 67000Strasbourg France
- Fédération de Médecine Translationnelle de Strasbourg (FMTS)Strasbourg France
- Twitter: @PE_Lutz
| | - Philippe Courtet
- INSERM, University of Montpellier, Neuropsychiatry, Epidemiological and Clinical ResearchMontpellier France
- Department of Emergency Psychiatry and Post‐Acute CareLapeyronie Hospital, CHU MontpellierMontpellier France
- FondaMental FoundationCréteil France
| | - Raffaella Calati
- INSERM, University of Montpellier, Neuropsychiatry, Epidemiological and Clinical ResearchMontpellier France
- Department of Emergency Psychiatry and Post‐Acute CareLapeyronie Hospital, CHU MontpellierMontpellier France
- FondaMental FoundationCréteil France
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25
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Smith CJW, Wilkins KB, Li S, Tulimieri MT, Veenema AH. Nucleus accumbens mu opioid receptors regulate context-specific social preferences in the juvenile rat. Psychoneuroendocrinology 2018; 89:59-68. [PMID: 29331800 DOI: 10.1016/j.psyneuen.2017.12.017] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2017] [Revised: 12/21/2017] [Accepted: 12/21/2017] [Indexed: 02/08/2023]
Abstract
The μ opioid receptor (MOR) in the nucleus accumbens (NAc) is involved in assigning pleasurable, or hedonic value to rewarding stimuli. Importantly, the hedonic value of a given rewarding stimulus likely depends on an individual's current motivational state. Here, we examined the involvement of MORs in the motivation to interact with a novel or a familiar (cage mate) conspecific in juvenile rats. First, we demonstrated that the selective MOR antagonist CTAP administered into the NAc reduces social novelty preference of juvenile males, by decreasing the interaction time with the novel conspecific and increasing the interaction time with the cage mate. Next, we found that a 3-h separation period from the cage mate reduces social novelty preference in both juvenile males and females, which was primarily driven by an increase in interaction time with the cage mate. Last, we showed that MOR agonism (intracerebroventricularly or in the NAc) restored social novelty preference in juvenile males that did not show social novelty preference following social isolation. Taken together, these data support a model in which endogenous MOR activation in the NAc facilitates the relative hedonic value of novel over familiar social stimuli. Our results may implicate the MOR in neuropsychiatric disorders characterized by altered social motivation, such as major depression and autism spectrum disorder.
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Affiliation(s)
- Caroline J W Smith
- Neurobiology of Social Behavior Laboratory, Department of Psychology, Boston College, 140 Commonwealth Ave, Chestnut Hill, MA, 02467, USA.
| | - Kevin B Wilkins
- Neurobiology of Social Behavior Laboratory, Department of Psychology, Boston College, 140 Commonwealth Ave, Chestnut Hill, MA, 02467, USA
| | - Sara Li
- Neurobiology of Social Behavior Laboratory, Department of Psychology, Boston College, 140 Commonwealth Ave, Chestnut Hill, MA, 02467, USA
| | - Maxwell T Tulimieri
- Neurobiology of Social Behavior Laboratory, Department of Psychology, Boston College, 140 Commonwealth Ave, Chestnut Hill, MA, 02467, USA
| | - Alexa H Veenema
- Neurobiology of Social Behavior Laboratory, Department of Psychology, Boston College, 140 Commonwealth Ave, Chestnut Hill, MA, 02467, USA
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26
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Heshmati M, Aleyasin H, Menard C, Christoffel DJ, Flanigan ME, Pfau ML, Hodes GE, Lepack AE, Bicks LK, Takahashi A, Chandra R, Turecki G, Lobo MK, Maze I, Golden SA, Russo SJ. Cell-type-specific role for nucleus accumbens neuroligin-2 in depression and stress susceptibility. Proc Natl Acad Sci U S A 2018; 115:1111-1116. [PMID: 29339486 PMCID: PMC5798379 DOI: 10.1073/pnas.1719014115] [Citation(s) in RCA: 47] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Behavioral coping strategies are critical for active resilience to stress and depression; here we describe a role for neuroligin-2 (NLGN-2) in the nucleus accumbens (NAc). Neuroligins (NLGN) are a family of neuronal postsynaptic cell adhesion proteins that are constituents of the excitatory and inhibitory synapse. Importantly, NLGN-3 and NLGN-4 mutations are strongly implicated as candidates underlying the development of neuropsychiatric disorders with social disturbances such as autism, but the role of NLGN-2 in neuropsychiatric disease states is unclear. Here we show a reduction in NLGN-2 gene expression in the NAc of patients with major depressive disorder. Chronic social defeat stress in mice also decreases NLGN-2 selectively in dopamine D1-positive cells, but not dopamine D2-positive cells, within the NAc of stress-susceptible mice. Functional NLGN-2 knockdown produces bidirectional, cell-type-specific effects: knockdown in dopamine D1-positive cells promotes subordination and stress susceptibility, whereas knockdown in dopamine D2-positive cells mediates active defensive behavior. These findings establish a behavioral role for NAc NLGN-2 in stress and depression; provide a basis for targeted, cell-type specific therapy; and highlight the role of active behavioral coping mechanisms in stress susceptibility.
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MESH Headings
- Aggression
- Animals
- Antidepressive Agents/pharmacology
- Behavior, Animal
- Cell Adhesion Molecules, Neuronal/metabolism
- Cell Line
- Depressive Disorder, Major/physiopathology
- Disease Models, Animal
- Dominance-Subordination
- Heterozygote
- Humans
- Male
- Mice
- Mice, Inbred C57BL
- Mice, Transgenic
- MicroRNAs/metabolism
- Nerve Tissue Proteins/metabolism
- Nucleus Accumbens/metabolism
- RNA, Messenger/metabolism
- Receptors, Dopamine D1/metabolism
- Receptors, Dopamine D2/metabolism
- Social Behavior
- Stress, Psychological/physiopathology
- Synapses/metabolism
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Affiliation(s)
- Mitra Heshmati
- Fishberg Department of Neuroscience, Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029
- Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029
| | - Hossein Aleyasin
- Fishberg Department of Neuroscience, Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029
- Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029
| | - Caroline Menard
- Fishberg Department of Neuroscience, Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029
- Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029
| | - Daniel J Christoffel
- Nancy Pritzker Laboratory, Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA 94305
| | - Meghan E Flanigan
- Fishberg Department of Neuroscience, Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029
- Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029
| | - Madeline L Pfau
- Fishberg Department of Neuroscience, Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029
- Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029
| | - Georgia E Hodes
- Fishberg Department of Neuroscience, Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029
- Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029
| | - Ashley E Lepack
- Fishberg Department of Neuroscience, Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029
- Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029
| | - Lucy K Bicks
- Fishberg Department of Neuroscience, Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029
- Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029
| | - Aki Takahashi
- Fishberg Department of Neuroscience, Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029
- Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029
- Laboratory of Behavioral Neuroendocrinology, University of Tsukuba, Ibaraki 305-8577, Japan
| | - Ramesh Chandra
- Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, MD 21201
| | - Gustavo Turecki
- McGill Group for Suicide Studies, Douglas Mental Health University Institute, McGill University, Montreal, QC H3A 0G4, Canada
| | - Mary Kay Lobo
- Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, MD 21201
| | - Ian Maze
- Fishberg Department of Neuroscience, Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029
- Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029
| | - Sam A Golden
- Behavioral Neuroscience Branch, Intramural Research Program, NIDA-NIH, Baltimore, MD 21224
| | - Scott J Russo
- Fishberg Department of Neuroscience, Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029;
- Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029
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27
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Colonnello V, Petrocchi N, Farinelli M, Ottaviani C. Positive Social Interactions in a Lifespan Perspective with a Focus on Opioidergic and Oxytocinergic Systems: Implications for Neuroprotection. Curr Neuropharmacol 2018; 15:543-561. [PMID: 27538784 PMCID: PMC5543675 DOI: 10.2174/1570159x14666160816120209] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2015] [Revised: 03/05/2016] [Accepted: 08/14/2016] [Indexed: 12/19/2022] Open
Abstract
In recent years, a growing interest has emerged in the beneficial effects of positive social interactions on health. The present work aims to review animal and human studies linking social interactions and health throughout the lifespan, with a focus on current knowledge of the possible mediating role of opioids and oxytocin. During the prenatal period, a positive social environment contributes to regulating maternal stress response and protecting the fetus from exposure to maternal active glucocorticoids. Throughout development, positive social contact with the caregiver acts as a “hidden regulator” and promotes infant neuroaffective development. Postnatal social neuroprotection interventions involving caregiver–infant physical contact seem to be crucial for rescuing preterm infants at risk for neurodevelopmental disorders. Attachment figures and friendships in adulthood continue to have a protective role for health and brain functioning, counteracting brain aging. In humans, implementation of meditative practices that promote compassionate motivation and prosocial behavior appears beneficial for health in adolescents and adults. Human and animal studies suggest the oxytocinergic and opioidergic systems are important mediators of the effects of social interactions. However, most of the studies focus on a specific phase of life (i.e., adulthood). Future studies should focus on the role of opioids and oxytocin in positive social interactions adopting a lifespan perspective.
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Affiliation(s)
- Valentina Colonnello
- Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna. Italy
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28
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Collins D, Randesi M, da Rosa JC, Zhang Y, Kreek MJ. Oprm1 A112G, a single nucleotide polymorphism, alters expression of stress-responsive genes in multiple brain regions in male and female mice. Psychopharmacology (Berl) 2018; 235:2703-2711. [PMID: 30027498 PMCID: PMC6132675 DOI: 10.1007/s00213-018-4965-x] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2018] [Accepted: 07/02/2018] [Indexed: 12/12/2022]
Abstract
BACKGROUND OPRM1 A118G, a functional human mu-opioid receptor (MOR) polymorphism, is associated with drug dependence and altered stress responsivity in humans as well as altered MOR signaling. MOR signaling can regulate many cellular processes, including gene expression, and many of the long-term, stable effects of drugs and stress may stem from changes in gene expression in diverse brain regions. A mouse model bearing an equivalent polymorphism (Oprm1 A112G) was previously generated and studied. Mice homozygous for the G112 allele show differences in opioid- and stress-related phenotypes. APPROACH The current study examines the expression of 24 genes related to drug and stress responsivity in the caudoputamen, nucleus accumbens, hypothalamus, hippocampus, and amygdala of drug-naïve, stress-minimized, male and female mice homozygous for either the G112 variant allele or the wild-type A112 allele. RESULTS We detected nominal genotype-dependent changes in gene expression of multiple genes. We also detected nominal sex-dependent as well as sex-by-genotype interaction effects on gene expression. Of these, four genotype-dependent differences survived correction for multiple testing: Avp and Gal in the hypothalamus and Oprl1 and Cnr1 in the hippocampus. CONCLUSIONS Changes in the regulation of these genes by mu-opioid receptors encoded by the G112 allele may be involved in some of the behavioral and molecular consequences of this polymorphism observed in mice.
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Affiliation(s)
- Devon Collins
- The Laboratory of the Biology of Addictive Diseases, The Rockefeller University, 1230 York Avenue, New York, NY, 10065, USA.
| | - Matthew Randesi
- 0000 0001 2166 1519grid.134907.8The Laboratory of the Biology of Addictive Diseases, The Rockefeller University, 1230 York Avenue, New York, NY 10065 USA
| | - Joel Correa da Rosa
- 0000 0001 2166 1519grid.134907.8Laboratory of Investigative Dermatology, The Rockefeller University, 1230 York Avenue, New York, NY 10065 USA
| | - Yong Zhang
- 0000 0001 2166 1519grid.134907.8The Laboratory of the Biology of Addictive Diseases, The Rockefeller University, 1230 York Avenue, New York, NY 10065 USA
| | - Mary Jeanne Kreek
- 0000 0001 2166 1519grid.134907.8The Laboratory of the Biology of Addictive Diseases, The Rockefeller University, 1230 York Avenue, New York, NY 10065 USA
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29
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Enkephalins: Endogenous Analgesics with an Emerging Role in Stress Resilience. Neural Plast 2017; 2017:1546125. [PMID: 28781901 PMCID: PMC5525068 DOI: 10.1155/2017/1546125] [Citation(s) in RCA: 56] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2017] [Revised: 05/15/2017] [Accepted: 05/24/2017] [Indexed: 12/20/2022] Open
Abstract
Psychological stress is a state of mental or emotional strain or tension that results from adverse or demanding circumstances. Chronic stress is well known to induce anxiety disorders and major depression; it is also considered a risk factor for Alzheimer's disease. Stress resilience is a positive outcome that is associated with preserved cognition and healthy aging. Resilience presents psychological and biological characteristics intrinsic to an individual conferring protection against the development of psychopathologies in the face of adversity. How can we promote or improve resilience to chronic stress? Numerous studies have proposed mechanisms that could trigger this desirable process. The roles of enkephalin transmission in the control of pain, physiological functions, like respiration, and affective disorders have been studied for more than 30 years. However, their role in the resilience to chronic stress has received much less attention. This review presents the evidence for an emerging involvement of enkephalin signaling through its two associated opioid receptors, μ opioid peptide receptor and δ opioid peptide receptor, in the natural adaptation to stressful lifestyles.
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30
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Sweeney CG, Rando JM, Panas HN, Miller GM, Platt DM, Vallender EJ. Convergent Balancing Selection on the Mu-Opioid Receptor in Primates. Mol Biol Evol 2017; 34:1629-1643. [PMID: 28333316 PMCID: PMC6279279 DOI: 10.1093/molbev/msx105] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Abstract
The mu opioid receptor is involved in many natural processes including stress response, pleasure, and pain. Mutations in the gene also have been associated with opiate and alcohol addictions as well as with responsivity to medication targeting these disorders. Two common and mutually exclusive polymorphisms have been identified in humans, A118G (N40D), found commonly in non-African populations, and C17T (V6A), found almost exclusively in African populations. Although A118G has been studied extensively for associations and in functional assays, C17T is much less well understood. In addition to a parallel polymorphism previously identified in rhesus macaques (Macaca mulatta), C77G (P26R), resequencing in additional non-human primate species identifies further common variation: C140T (P47L) in cynomolgus macaques (Macaca fascicularis), G55C (D19H) in vervet monkeys (Chlorocebus aethiops sabeus), A111T (L37F) in marmosets (Callithrix jacchus), and C55T (P19S) in squirrel monkeys (Saimiri boliviensis peruviensis). Functional effects on downstream signaling are observed for each of these variants following treatment with the endogenous agonist β-endorphin and the exogenous agonists morphine, DAMGO ([d-Ala2, N-Me-Phe4, Gly5-ol]-enkephalin), and fentanyl. In addition to demonstrating the importance of functional equivalency in reference to population variation for minority health, this also shows how common evolutionary pressures have produced similar phenotypes across species, suggesting a shared response to environmental needs and perhaps elucidating the mechanism by which these organism-environment interactions are mediated physiologically and molecularly. These studies set the stage for future investigations of shared functional polymorphisms across species as a new genetic tool for translational research.
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Affiliation(s)
- Carolyn G. Sweeney
- Division of Neuroscience, New England Primate Research Center, Harvard Medical School, Southborough, MA
| | - Juliette M. Rando
- Division of Neuroscience, New England Primate Research Center, Harvard Medical School, Southborough, MA
| | - Helen N. Panas
- Division of Neuroscience, New England Primate Research Center, Harvard Medical School, Southborough, MA
| | - Gregory M. Miller
- Division of Neuroscience, New England Primate Research Center, Harvard Medical School, Southborough, MA
| | - Donna M. Platt
- Division of Neuroscience, New England Primate Research Center, Harvard Medical School, Southborough, MA
| | - Eric J. Vallender
- Division of Neuroscience, New England Primate Research Center, Harvard Medical School, Southborough, MA
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31
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Pellissier LP, Gandía J, Laboute T, Becker JAJ, Le Merrer J. μ opioid receptor, social behaviour and autism spectrum disorder: reward matters. Br J Pharmacol 2017; 175:2750-2769. [PMID: 28369738 DOI: 10.1111/bph.13808] [Citation(s) in RCA: 63] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2017] [Revised: 03/10/2017] [Accepted: 03/24/2017] [Indexed: 12/19/2022] Open
Abstract
The endogenous opioid system is well known to relieve pain and underpin the rewarding properties of most drugs of abuse. Among opioid receptors, the μ receptor mediates most of the analgesic and rewarding properties of opioids. Based on striking similarities between social distress, physical pain and opiate withdrawal, μ receptors have been proposed to play a critical role in modulating social behaviour in humans and animals. This review summarizes experimental data demonstrating such role and proposes a novel model, the μ opioid receptor balance model, to account for the contribution of μ receptors to the subtle regulation of social behaviour. Interestingly, μ receptor null mice show behavioural deficits similar to those observed in patients with autism spectrum disorder (ASD), including severe impairment in social interactions. Therefore, after a brief summary of recent evidence for blunted (social) reward processes in subjects with ASD, we review here arguments for altered μ receptor function in this pathology. This article is part of a themed section on Emerging Areas of Opioid Pharmacology. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.14/issuetoc.
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Affiliation(s)
- Lucie P Pellissier
- Physiologie de la Reproduction et des Comportements, INRA UMR-0085, CNRS UMR-7247, Université de Tours Rabelais, IFCE, Inserm, Nouzilly, France
| | - Jorge Gandía
- Physiologie de la Reproduction et des Comportements, INRA UMR-0085, CNRS UMR-7247, Université de Tours Rabelais, IFCE, Inserm, Nouzilly, France
| | - Thibaut Laboute
- Physiologie de la Reproduction et des Comportements, INRA UMR-0085, CNRS UMR-7247, Université de Tours Rabelais, IFCE, Inserm, Nouzilly, France
| | - Jérôme A J Becker
- Physiologie de la Reproduction et des Comportements, INRA UMR-0085, CNRS UMR-7247, Université de Tours Rabelais, IFCE, Inserm, Nouzilly, France
| | - Julie Le Merrer
- Physiologie de la Reproduction et des Comportements, INRA UMR-0085, CNRS UMR-7247, Université de Tours Rabelais, IFCE, Inserm, Nouzilly, France
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32
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Browne CA, Erickson RL, Blendy JA, Lucki I. Genetic variation in the behavioral effects of buprenorphine in female mice derived from a murine model of the OPRM1 A118G polymorphism. Neuropharmacology 2017; 117:401-407. [PMID: 28188737 DOI: 10.1016/j.neuropharm.2017.02.005] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2016] [Revised: 02/05/2017] [Accepted: 02/06/2017] [Indexed: 10/20/2022]
Abstract
Pharmacogenetic studies have identified the non-synonymous single nucleotide polymorphism (A118G) in the human mu opioid receptor (MOR) gene (OPRM1) as a critical genetic variant capable of altering the efficacy of opioid therapeutics. To date few studies have explored the potential impact of the OPRM1 A118G polymorphism on the pharmacological effects of buprenorphine (BPN), a potent MOR partial agonist and kappa opioid receptor antagonist, which is approved by the FDA for the treatment of opioid addiction and chronic pain. The goal of these studies was to determine whether the MOR-mediated behavioral effects of BPN were altered in the Oprm1 A112G mouse model of the human OPRM1 A118G SNP. All studies were conducted in female, AA, AG and GG mice. BPN's maximal analgesic effect in the hot plate test was significantly blunted in AG and GG mice compared to wild type AA mice. Similarly, the BPN-induced reduction of latency to consume food in the novelty induced hypophagia test was blocked entirely in AG and GG mice compared to their AA littermates. In addition, GG mice exhibited marked reductions in psychostimulant hyperlocomotor activity compared to the AA group. In contrast, reduced immobility in the forced swim test, an effect of BPN mediated by kappa opioid receptors, was not affected by genotype. These studies demonstrate the ability of the Oprm1 A112G SNP to attenuate the analgesic, anxiolytic and hyperlocomotor effects of BPN. Overall, these data suggest that the OPRM1 A118G SNP will significantly impact the clinical efficacy of BPN in its therapeutic applications.
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Affiliation(s)
- Caroline A Browne
- Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, United States.
| | - Rebecca L Erickson
- Department of Pathobiology, University of Pennsylvania, Philadelphia, PA, United States
| | - Julie A Blendy
- Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, PA, United States
| | - Irwin Lucki
- Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, United States; Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, PA, United States
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33
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Abstract
This paper is the thirty-eighth consecutive installment of the annual review of research concerning the endogenous opioid system. It summarizes papers published during 2015 that studied the behavioral effects of molecular, pharmacological and genetic manipulation of opioid peptides, opioid receptors, opioid agonists and opioid antagonists. The particular topics that continue to be covered include the molecular-biochemical effects and neurochemical localization studies of endogenous opioids and their receptors related to behavior, and the roles of these opioid peptides and receptors in pain and analgesia, stress and social status, tolerance and dependence, learning and memory, eating and drinking, drug abuse and alcohol, sexual activity and hormones, pregnancy, development and endocrinology, mental illness and mood, seizures and neurologic disorders, electrical-related activity and neurophysiology, general activity and locomotion, gastrointestinal, renal and hepatic functions, cardiovascular responses, respiration and thermoregulation, and immunological responses.
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Affiliation(s)
- Richard J Bodnar
- Department of Psychology and Neuropsychology Doctoral Sub-Program, Queens College, City University of New York, Flushing, NY 11367, United States.
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34
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Chelnokova O, Laeng B, Løseth G, Eikemo M, Willoch F, Leknes S. The µ-opioid system promotes visual attention to faces and eyes. Soc Cogn Affect Neurosci 2016; 11:1902-1909. [PMID: 27531386 DOI: 10.1093/scan/nsw116] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2016] [Revised: 07/17/2016] [Accepted: 08/10/2016] [Indexed: 12/25/2022] Open
Abstract
Paying attention to others' faces and eyes is a cornerstone of human social behavior. The µ-opioid receptor (MOR) system, central to social reward-processing in rodents and primates, has been proposed to mediate the capacity for affiliative reward in humans. We assessed the role of the human MOR system in visual exploration of faces and eyes of conspecifics. Thirty healthy males received a novel, bidirectional battery of psychopharmacological treatment (an MOR agonist, a non-selective opioid antagonist, or placebo, on three separate days). Eye-movements were recorded while participants viewed facial photographs. We predicted that the MOR system would promote visual exploration of faces, and hypothesized that MOR agonism would increase, whereas antagonism decrease overt attention to the information-rich eye region. The expected linear effect of MOR manipulation on visual attention to the stimuli was observed, such that MOR agonism increased while antagonism decreased visual exploration of faces and overt attention to the eyes. The observed effects suggest that the human MOR system promotes overt visual attention to socially significant cues, in line with theories linking reward value to gaze control and target selection. Enhanced attention to others' faces and eyes represents a putative behavioral mechanism through which the human MOR system promotes social interest.
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Affiliation(s)
- Olga Chelnokova
- Department of Psychology, University of Oslo, Oslo N-0317, Norway
| | - Bruno Laeng
- Department of Psychology, University of Oslo, Oslo N-0317, Norway
| | - Guro Løseth
- Department of Psychology, University of Oslo, Oslo N-0317, Norway
| | - Marie Eikemo
- Department of Psychology, University of Oslo, Oslo N-0317, Norway.,Norwegian Center for Addiction Research, University of Oslo, Oslo N-0318, Norway.,Division of Mental Health and Addiction, Oslo University Hospital, Oslo N-0318, Norway
| | - Frode Willoch
- Department of Medicine, University of Oslo, Oslo N-0316, Norway
| | - Siri Leknes
- Department of Psychology, University of Oslo, Oslo N-0317, Norway.,Department of Medicine, University of Oslo, Oslo N-0316, Norway.,The Intervention Centre, Oslo University Hospital, Oslo N-0424, Norway
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35
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Mague SD, Port RG, McMullen ME, Carlson GC, Turner JR. Mouse model of OPRM1 (A118G) polymorphism has altered hippocampal function. Neuropharmacology 2015; 97:426-35. [PMID: 25986698 DOI: 10.1016/j.neuropharm.2015.04.032] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2014] [Revised: 04/08/2015] [Accepted: 04/27/2015] [Indexed: 01/08/2023]
Abstract
A single nucleotide polymorphism (SNP) in the human μ-opioid receptor gene (OPRM1 A118G) has been widely studied for its association in a variety of drug addiction and pain sensitivity phenotypes; however, the extent of these adaptations and the mechanisms underlying these associations remain elusive. To clarify the functional mechanisms linking the OPRM1 A118G SNP to altered phenotypes, we used a mouse model possessing the equivalent nucleotide/amino acid substitution in the Oprm1 gene. In order to investigate the impact of this SNP on circuit function, we used voltage-sensitive dye imaging in hippocampal slices and in vivo electroencephalogram recordings of the hippocampus following MOPR activation. As the hippocampus contains excitatory pyramidal cells whose activity is highly regulated by a dense network of inhibitory neurons, it serves as an ideal structure to evaluate how putative receptor function abnormalities may influence circuit activity. We found that MOPR activation increased excitatory responses in wild-type animals, an effect that was significantly reduced in animals possessing the Oprm1 SNP. Furthermore, in order to assess the in vivo effects of this SNP during MOPR activation, EEG recordings of hippocampal activity following morphine administration corroborated a loss-of-function phenotype. In conclusion, as these mice have been shown to have similar MOPR expression in the hippocampus between genotypes, these data suggest that the MOPR A118G SNP results in a loss of receptor function.
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Affiliation(s)
- Stephen D Mague
- Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA
| | - Russell G Port
- Department of Psychiatry, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA
| | - Michael E McMullen
- Department of Psychiatry, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA
| | - Greg C Carlson
- Department of Psychiatry, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA
| | - Jill R Turner
- Department of Drug Discovery and Biomedical Sciences, South Carolina College of Pharmacy, University of South Carolina, Columbia, SC 29036, USA.
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