Clinical double-blind placebo-controlled studies have shown that naltrexone significantly reduced relapse rates and alcohol consumption in treated alcoholic patients compared to placebo-treated alcoholics. Similar preliminary results have been demonstrated with the opioid antagonist nalmefene versus placebo. At a recent symposium on the mechanisms of opioid antagonist treatment to reduce drinking, it was suggested that the identification of individuals most likely to benefit from such treatment and the development of increasingly selective pharmacological adjuncts may relate to changes in the stress responsivity axis and concomitant subjective changes. Both opioid antagonists and acute alcohol have been found to activate the hypothalamic-pituitary- adrenal axis, however subgroups at risk for alcoholism have shown differential activation and/or neuroadaptation. We propose to examine the effect of the opioid antagonists naloxone and nalmefene on both subjective report and HPA axis responsivity, which may provide the individual with an internal """"""""cue"""""""" and precede other changes associated with subjective intoxication. The use of naloxone, a short-acting antagonist primarily acting at mu opioid receptors, and nalmefene, a mu and kappa receptor agent, will allow further analysis of receptor subtype activity. In lieu of our recent study demonstrating a differential response to naltrexone in sons of alcoholics versus sons of nonalcoholics, participants for this study will include abstinent alcoholics (greater than or equal to l month sober), and heavy consumption social drinkers at High- and Low- Risk for the future development of alcohol dependence based on family history, as well as normal low-consumption Lower-Risk control subjects. The groups will be compared on neuroendocrine (ACTH, cortisol, beta-endorphin) and subjective (POMS, Karolinska Scale) measures during baseline (saline injection) conditions and separate sessions pre- and post-administration of i.v. 30 mg naloxone and nalmefene. The High Risk model has been used previously to aid in identification of psychobiological markers and motivational implications of problematic drinking, and the paradigm may also be of benefit for the study of pharmacological agents. Our long-term objectives are to acquire a database with which to further study the mechanisms and perturbations in HPA function and subjective response to opioid antagonist treatment in alcoholics and heavy consumption drinkers at risk for the disorder.
| King, Andrea C; Schluger, James; Gunduz, Mithat et al. (2002) Hypothalamic-pituitary-adrenocortical (HPA) axis response and biotransformation of oral naltrexone: preliminary examination of relationship to family history of alcoholism. Neuropsychopharmacology 26:778-88 |
