Alcohol has clear effects on the opioid system. Individuals with a family history of alcoholism have a greater b-endorphin response to alcohol than controls and naltrexone reduces the stimulant effects of alcohol only in individuals with a family history of alcoholism. Genetic variations in the u-opioid receptor system have been associated with alcoholism. A genetic variation with increased binding and agonist activation of the mu opioid receptor increases craving for alcohol, and alcoholics with high alcohol craving respond better to naltrexone treatment than those with low craving. Heavy drinkers with this genetic variant have a reduced alcohol induced high following naltrexone than those without, and alcoholics with this variant have a better treatment response to treatment with naltrexone. The data suggest that genetic variations that increase opioid activity increase dopamine release and increase the risk of alcoholism and improve the treatment response to opioid antagonists
A family history of alcoholism increases the B-endorphin response to alcohol.

Individuals with a Family History of Alcoholism Have Increased Pituitary ß-Endorphin Response to Alcohol

20 high risk white subjects (50% female, 20 – 30 years of age) with minimum of 2 generations history of alcoholism who drank an average of 7.6 days/month and 20 low risk white subjects (50% female) with no family history of alcoholism who drank an average of 7.4 days/month, drank placebo and 3 doses of alcohol (above) on 4 separate days. Peak blood alcohol was about .03, .08 and .12 gm/100 mL for the 3 doses. Alcohol did not change plasma cortisol levels in either group. (Constructed from data in Gianoulakis, C. et al. Arch Gen Psychiatry, 53: 250, 1966) ©2008 NBEP
A family history of alcoholism increases the effect of naltrexone

Naltrexone Reduces Stimulant Effects of Alcohol Only in Individuals with a Family History of Alcohol Dependence

From male social drinkers between 21 – 31 years of age (low risk) with no history of relatives with alcohol dependence in the last 2 generations and 15 (high risk) with fathers and other relatives with alcohol dependence, received naltrexone(50 mgm, oral) or placebo 3 ½ hours before drinking alcohol 0.6 gm/100 ml (peak blood alcohol was .06 gm/100 ml). Naltrexone did not alter alcohol-induced changes in sedation ratings. (Constructed from data in King, A.C. et al. Psychopharmacology, 129: 15, 1997) ©2008 NBEP
Individuals with a variant in the u-opioid receptor gene have an increased response to naltrexone.

A μ-Opioid Receptor Gene (OPRMI) Polymorphism Predicts an Increase Effect of Naltrexone on Reducing Alcohol Induced “High” in Heavy Drinkers and an Improved Treatment Response to Naltrexone in Alcoholism

Study A: 40 individuals (12 women) mean age 22 who were heavy drinkers took naltrexone (50 mgm/day for 3 days) or placebo before receiving intravenous alcohol to raise blood alcohol to .02, .04 and .06 gm/100 ml at which time rating scales were completed. Following placebo, alcohol produced increased ratings of “high” in those that carried a G allele and naltrexone had a larger effect in reducing the alcohol induced “high” in the G allele carrying group. (Constructed from data in Ray, L.A. and Hutchinson, K.E. et al. Arch General Psychiatry, 64: 1069, 2007)Study B: 604 Caucasian individuals (mean age 45, about 70% male) with a primary diagnosis of alcohol dependence took part in a large multi site study of combined pharmacotherapies and behavioral interventions for alcohol dependence. They all received medical management, about ½ also received combined behavioral intervention (CBI). About ½ took naltrexone 100 mgm/day and ½ placebo for 16 weeks. Significant effects of naltrexone were not seen in those receiving medical management plus CBI. (Constructed from data in Anton, R.F. et al. Arch General Psychiatry, 65: 135, 2008) ©2008 NBEP
The variant in the u-opioid receptor increases craving and improves treatment response to naltrexone.

In male drinkers a genetic variant with increased binding and agonist activation of the mu opiod receptor increases craving for alcohol. In alcohol dependent patients those with higher pretreatment alcohol craving and those with the genetic variant have a better treatment response to the mu receptor antagonist naltrexone

In (A), craving was measured in 108 alcohol drinkers (over 20 drinks/week) after a 3 min exposure to water or beer. Exposure to beer increased craving and there was no difference in craving between genotypes to water exposure. In (B), 121 alcohol dependent patients received naltrexone and 62 received placebo for 12 weeks. Pretreatment alcohol craving measured on the Penn alcohol craving scale. Patients were assigned to Low, Moderate or High craving groups. In (C), 71 patients had 12 week of treatment with naltrexone and 59 with placebo. (Constructed from data in (A)Van den Wildenberg, E. et al. Alcoholism: Clinical and Experimental Research, 31: 1, 2007; (B) Monterosso, J.R. et al. American J on Addictions, 10: 258, 2001; (C) Oslin, D.W. et al. Neuropsychopharmacology, 28: 1546, 2003) ©2007 NBEP
The increase in dopamine release with the u-receptor variant can explain the increased preference for alcohol and response to naltrexone.

A Genetic Variant of the Mu Opioid Receptor Increases Alcohol Induced Dopamine Release in the Ventral Striatum and Increases Alcohol Preference that is Selectively Decreased by Naltrexone

(A)Human subjects receive placebo or IV alcohol to raise BAC to 80 mg/100 ml over 15 min. Dopamine release was measured using positron emission tomography and 11C raclopride displacement. Significant alcohol induced release was found in both the anterior and posterior ventral striatum but not in caudate or putamen. Mouse lines were generated to carry the AA or GG human sequence variant. Dopamine release was measured by brain micro dialysis in ventral striatum/nucleus accumbens following alcohol 2 g/kg IP.(Constructed from data in Ramchandan, V.A. et al. Molecular Psychiatry online pub. 18 May 2010)(B)In rhesus monkeys a single nucleotide polymorphism in the mu opioid receptor gene (C77G) isfunctionally equivalent to the human A118G polymorphism. Alcohol preference compared to vehicle was measured in the home cage of 21 monkeys. Monkeys receive saline or naltrexone (1 mg/kg) 1m 1 hr before preference testing.(Constructed from data in Barr, C.S. et al. Bio Psychiatry 67: 78, 2010) ©2010 NBEP