Genetic analysis of the mu-opioid receptor in alcohol-dependent individuals

On the basis of various study results, it is suggested that the ethanol-ind uced activation of the endogenous opioid system may play an important role in mediating the reinforcing effects of ethanol. The mesolimbic dopamine re ward system is activated by both ethanol and opioids, and genetic differenc es in the sensitivity of the endogenous opioid system to alcohol may be an important factor determining the risk for the development of excessive alco hol consumption. Thus, variants of the mu -opioid receptor (mu OR) gene may confer vulnerability to alcohol dependence. Five exon 1 variants of the mu OR were investigated in 327 alcohol-dependent and 340 healthy control subj ects. The Val6 variant of the +17C/T polymorphism and the Asp40 variant of the +118A/G polymorphism showed a trend to an increased allele frequency in alcohol-dependent subjects. The latter polymorphism was investigated in mo re detail. The dopamine receptor agonist apomorphine causes an increase in growth hormone (GH) levels in the blood by stimulating the release of growt h hormone-releasing hormone. beta -endorphin also activates this regulatory circuit. We found a blunted response in intoxicated alcohol-dependent subj ects, but no difference in GH response between the groups of alcohol-depend ent subjects with and without the variant Asp allele. However, alcohol-depe ndent subjects with the Asp allele showed a significantly higher GH respons e at day 7 after alcohol withdrawal and a tendency to lower novelty seeking . These results suggest to us that there is reduced dopaminergic neuronal a ctivity in alcohol-dependent subjects with the mu OR Asp40 allele, along wi th a compensating increase in dopamine receptor activity. The difference be tween the two groups of alcohol-dependent subjects can be demonstrated only under certain conditions such as alcohol withdrawal, which necessitates th e adaptation of the neurones to a new homeostasis. (C) 2001 Elsevier Scienc e Inc. All rights reserved.