Opioid neurotransmission, HPA axis activation and risk of alcoholism

Date of Completion

January 2006


Biology, Neuroscience|Psychology, Psychobiology|Biology, Genetics




What are the neurohormonal and genetic factors involved in the risk for alcohol dependence (AD)? Evidence (reviewed in chapter I) suggests that heritable disturbances in opioid neurotransmission and HPA axis activity may explain such risk. Given that the opioidergic neurotransmitter system modulates HPA axis activity, pharmacological manipulation of this axis provides a noninvasive measure of central opioidergic tone. This approach appears to be of utility in evaluating the relationship between opioidergic function and genetic risk for AD. To gain insight into this relationship, we conducted three analyses in which a placebo-controlled, balanced, within-subject design was followed. The experiments involved two test days among healthy subjects who received intravenous naloxone or placebo. Plasma corticotropin and cortisol were measured for up to 120 min. post infusion. In Chapter II we examined the effects of paternal history of AD on neuronendocrine response to naloxone. Subjects with paternal history of AD (PHP) exhibited a greater cortisol response than those without such history. In Chapter III, we examined the effects of the functional mu-opioid receptor gene (OPRM1) polymorphism Asn40Asp. In this analysis, Asp40 alleles conferred a greater cortisol response to naloxone than Asn40 alleles. However, there were no interactive effects of Asp40 alleles with paternal history of AD. In Chapter IV, we examined whether the Asn40Asp variant had an effect in the development of personality dimensions associated with an increased risk of AD and/or drug dependence (DD). In this analysis, we did not find an association between this polymorphism and personality dimensions. Finally in Chapter V, we described a population-specific effect of the Asn40Asp polymorphism, in which European Americans (EAs) with Asp40 alleles had a greater cortisol response than Asn40 EAs and Asians in both genotype groups. A genotype X environment interaction and/or presence of other functional OPRM1 variants in linkage disequilibrium (LD) with Asn40Asp influencing opioid regulation of HPA axis activity are plausible explanations for this finding. In conclusion, our findings support the notion of a deficient opioid regulation of HPA axis activity associated with an increased risk for AD. Although Asp40 is a relevant variant affecting opioid neurotransmission, we failed to support the hypothesis that this polymorphism modulates risk of AD.^