Mouse Model of<i>OPRM1</i>(A118G) Polymorphism Increases Sociability and Dominance and Confers Resilience to Social Defeat

Briand, Lisa A.; Hilário, Monica R F; Dow, Holly C.; Brodkin, Edward S.; Blendy, Julie A.; Berton, Olivier

doi:10.1523/jneurosci.4685-14.2015

Cited by 38 publications

(30 citation statements)

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“…In humans, adult carriers of the A118G OPRM1 polymorphism show less avoidance of affectionate relationships and increased capacity to experience social reward (Troisi et al , ), whereas child carriers display improved relationships, better resilience to aversive parental care and enhanced responses to facial expression of social and emotional stimuli (Copeland et al , ; Troisi et al , ; Bertoletti et al , ). Consistent with this, A118G OPRM1 knock‐in mice exhibit increased social interaction, dominance and protection from social defeat (Mague et al , ; Briand et al , ). Similarly, the C77G polymorphism in macaques, equivalent to the human A118G polymorphism, results in higher affiliative behaviour in mothers and infants (Barr et al , ; Higham et al , ).…”

Section: Role Of μ Receptors Under Neutral/positive Social Conditionsmentioning

confidence: 72%

μ opioid receptor, social behaviour and autism spectrum disorder: reward matters

Pellissier

Gandía

Laboute

et al. 2017

British J Pharmacology

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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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Section: Role Of μ Receptors Under Neutral/positive Social Conditionsmentioning

confidence: 72%

μ opioid receptor, social behaviour and autism spectrum disorder: reward matters

Pellissier

Gandía

Laboute

et al. 2017

British J Pharmacology

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“…Mice possessing the equivalent SNP (A112G) have decreased MOPR expression and morphine-evoked behaviors, altered GTPγS binding to the MOPR and downstream intracellular signaling cascades, and sex-specific deficits in morphine reward (Knapman et al, 2014; Mague et al, 2009; Wang et al, 2014; Wang et al, 2012). Additionally, recent studies in humans possessing the A118G SNP (Troisi et al, 2012; Way et al, 2010; Way et al, 2009) and in this mouse model of the A118G SNP (Briand et al, 2015) have shown in parallel that this SNP may have important ramifications for more complex behaviors, such as stress resiliency, which would also impact relapse behaviors in addiction. However, it has not been determined whether these effects result from decreased receptor availability or altered receptor function.…”

Section: Introductionmentioning

confidence: 89%

Mouse model of OPRM1 (A118G) polymorphism has altered hippocampal function

et al. 2015

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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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“…1A). In addition, it has been shown previously that the G allele is associated with an increase in home-cage dominance and increased motivation for nonaggressive social interactions (Briand et al, 2015); and it has also been shown that G-allele carrier mice have attenuated analgesic, anxiolytic, and hyperlocomotive effects from buprenorphine (Browne et al, 2017). In the humanized Oprm1 A118G mouse model, it has been shown that the effects of opioid antagonism on alcohol reward and consumption are affected (Bilbao et al, 2015).…”

Section: Behavioral Alterations In Rodent Models Of Oprm1 A118g Snpsmentioning

confidence: 97%

“…A loss of function in the minor allele caused differential outcomes, which might account for the different reward behaviors induced by drugs of abuse ( Fig. 1A) (Ramchandani et al, 2011;Bilbao et al, 2015;Robinson et al, 2015;Zhang et al, 2015;Browne et al, 2017) or other types of behavior (Briand et al, 2015).…”

Section: Impact Of Oprm1 A118 Gene Variant (N40d Mors) On Synaptic Rementioning

confidence: 99%

“…Remarkably, these mice reproduce most of the phenotypes reported for the human OPRM1 SNP, including altered morphine-mediated antinociception, the rewarding properties of morphine, and the response to naloxone-precipitated morphine withdrawal. In addition, it was found that the Oprm1 A112G SNP alters MOR N-linked glycosylation and protein stability Wang et al, 2012), affects heroin self-administration (Zhang et al, 2015), increases sociability and dominance, and confers resilience to social defeat (Briand et al, 2015). However, the functional role of A118G in reward neurocircuitry remains elusive.…”

Section: Introductionmentioning

confidence: 99%

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Synaptic Regulation by OPRM1 Variants in Reward Neurocircuitry

et al. 2019

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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, ϳ25% 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 GABA B 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.The pandemic of opioid drug abuse is associated with many socioeconomic burdens. The primary brain target of opioid drugs is the -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 GABA B 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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Mouse Model ofOPRM1(A118G) Polymorphism Increases Sociability and Dominance and Confers Resilience to Social Defeat

Cited by 38 publications

References 50 publications

μ opioid receptor, social behaviour and autism spectrum disorder: reward matters

μ opioid receptor, social behaviour and autism spectrum disorder: reward matters

Mouse model of OPRM1 (A118G) polymorphism has altered hippocampal function

Synaptic Regulation by OPRM1 Variants in Reward Neurocircuitry

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