Synaptic Regulation by OPRM1 Variants in Reward Neurocircuitry

• Published in: The Journal of neuroscience Vol. 39; no. 29; pp. 5685 - 5696
• Main Authors: Popova, Dina, Desai, Nidhi, Blendy, Julie A, Pang, Zhiping P
• Format: Journal Article
• Language: English
• Published: United States Society for Neuroscience 17-07-2019
• Subjects: Action potential; Addictions; Alleles; Amino acid substitution; Animal models; Asparagine; Dopamine D4 receptors; Drug abuse; Drug addiction; Electrophysiology; Enkephalins; Firing rate; Mesolimbic system; Minority & ethnic groups; Morphine; Narcotics; Neurons; Nucleotides; Opioid receptors (type mu); Phenotypes; Polymorphism; Receptors; Reinforcement; Single-nucleotide polymorphism; Synaptic transmission; γ-Aminobutyric acid B receptors; MOR; VTA; SNP; opioid dependence
• ISSN: 0270-6474; 1529-2401
• DOI: 10.1523/JNEUROSCI.2317-18.2019

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,
Varying with ethnicity, ∼25% of humans carry a single nucleotide polymorphism (SNP) in
(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
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
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
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
gene, which is highly polymorphic in humans. Using a mouse model of the human
A118G single nucleotide polymorphism (SNP) (A112G in mice), we demonstrated that MOR and GABA
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.