Abstract
657
Objectives: The mu opioid receptor alters stress response and modulates alcohol consumption in animal and human studies through its effect on neural reward circuitry. This study used [18F]mefway to interrogate the 5-HT1A serotonergic system before and after fixed-dose ethanol exposure to further the understanding of the effect of the mu opioid receptor on neuroadaptation to drinking.
Methods: Twenty-three rhesus monkeys (Macaca mulatta; 19.1±0.8 yrs; 12M,11F) were reared under identical conditions. Subjects underwent an alcohol-naïve, pre-drinking [18F]mefway PET scan (90 min), then self-administered a fixed-dose of ethanol for 9 months, and underwent a post-drinking [18F]mefway scan. Subjects then underwent an ad libidum phase of ethanol self-administration for 2 months. Distribution volume ratios (DVRs) were estimated with MRTM2 using cerebellar gray matter as reference region (t[asterisk] = 40 min). Nine regions of interest (ROIs) from the 112RM-SL atlas (McLaren 2009) were chosen for analysis based on their involvement in salience and reward circuitry. Two variants of the mu opioid receptor gene (OPRM1) were present in this cohort. A single nucleotide polymorphism (SNP), occurs when a cysteine is replaced by a guanine at position 77 (C77G, referred to as CG; the typical OPRM1 will be referred to as CC), effectively replacing an arginine with a proline in the N-terminal arm. The Wilcoxon signed rank test was used to assess differences in DVR, as well as ad libidum drinking between wildtype and SNP OPRM1.
Results: Pre-drinking DVR was significantly different between OPRM1 variants (CG>CC) in the anterior cingulate (p=0.009), hippocampus (p=0.03), lateral prefrontal cortex (p=0.007), occipital lobe (p=0.02), parietal lobe (p=0.02), and temporal lobe (p=0.04). Similarly, the change in DVR was significantly different between OPRM1 variants (CG>CC) in the amygdala (p=0.03) and hippocampus (p=0.04). There was no significant difference in the average daily intake of alcohol during the ad libidum phase between OPRM1 variants (CC: 0.86±0.84 g/kg/day, CG: 1.10±0.60 g/kg/day).
Conclusion: The primate CG SNP corresponds to the human A118G SNP, which has been shown to correlate with greater subjective effects in response to alcohol in humans, and drinking to intoxication in primates (Haile 2008). The results demonstrate that subjects with the CG SNP had a higher density of 5-HT1A serotonin receptors in regions associated with salience and reward, and also a greater increase in receptor density following fixed-dose ethanol exposure. Research Support: NIH AA017706, NIH AA12277, NICHD U54 HD090256