title: Mouse model of OPRM1 (A118G) polymorphism increases sociability and dominance and confers resilience to social defeat.
abstract: A single nucleotide polymorphism (SNP) in the human μ-opioid receptor gene (OPRM1 A118G) has been widely studied for its association in drug addiction, pain sensitivity, and, more recently, social behavior. The endogenous opioid system has been shown to regulate social distress and reward in a variety of animal models. However, mechanisms underlying the associations between the OPRM1 A118G SNP and these behaviors have not been clarified. We used a mouse model possessing the human equivalent nucleotide/amino acid substitution to study social affiliation and social defeat behaviors. In mice with the Oprm1 A112G SNP, we demonstrate that the G allele is associated with an increase in home-cage dominance and increased motivation for nonaggressive social interactions, similar to what is reported in human populations. When challenged by a resident aggressor, G-allele carriers expressed less submissive behavior and exhibited resilience to social defeat, demonstrated by a lack of subsequent social avoidance and reductions in anhedonia as measured by intracranial self-stimulation. Protection from social defeat in G-allele carriers was associated with a greater induction of c-fos in a resilience circuit comprising the nucleus accumbens and periaqueductal gray. These findings led us to test the role of endogenous opioids in the A112G mice. We demonstrate that the increase in social affiliation in G carriers is blocked by pretreatment with naloxone. Together, these data suggest a mechanism involving altered hedonic state and neural activation as well as altered endogenous opioid tone in the differential response to aversive and rewarding social stimuli in G-allele carriers.
authors.affiliation: Department of Pharmacology and Department of Psychology, Temple University, Philadelphia, Pennsylvania 19122.
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Briand
authors.affiliation: Department of Pharmacology and.
authors.forename: Monica
authors.initials: M
authors.lastname: Hilario
authors.affiliation: Department of Psychiatry, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, and.
authors.forename: Holly C
authors.initials: HC
authors.lastname: Dow
authors.affiliation: Department of Psychiatry, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, and.
authors.forename: Edward S
authors.initials: ES
authors.lastname: Brodkin
authors.affiliation: Department of Pharmacology and blendy@mail.med.upenn.edu.
authors.forename: Julie A
authors.initials: JA
authors.lastname: Blendy
authors.affiliation: Department of Psychiatry, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, and.
authors.forename: Olivier
authors.initials: O
authors.lastname: Berton
mesh_terms: D000374:Aggression; D059445:Anhedonia; D000818:Animals; D004291:Dominance-Subordination; D005260:Female; D006579:Heterozygote; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020125:Mutation, Missense; D009270:Naloxone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D009714:Nucleus Accumbens / Q000378:metabolism / Q000502:physiology; D010487:Periaqueductal Gray / Q000378:metabolism / Q000502:physiology; D020641:Polymorphism, Single Nucleotide; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D009292:Narcotic Antagonists; C404943:Oprm protein, mouse; D016760:Proto-Oncogene Proteins c-fos; D017450:Receptors, Opioid, mu; D009270:Naloxone
keywords: OPRM1 A118G; anhedonia; intracranial self-stimulation; social defeat; social interaction; μ-opioid