Family History of Alcoholism Is Associated With Lower 5‐HT2A Receptor Binding in the Prefrontal Cortex

BACKGROUND: 5-Hydroxytryptophan (5-HT(2A)) receptor involvement in alcoholism is suggested by less 5-HT(2A) binding in alcohol preferring rats, association of a 5-HT(2A) receptor gene polymorphism with alcohol dependence and reduced alcohol intake with 5-HT(2A) antagonists. We sought to determine postmortem whether 5-HT(2A) receptors are altered in the prefrontal cortex (PFC) of alcoholics. METHODS: Brain tissue from 25 alcoholics and 19 controls was collected at autopsy. Diagnosis of DSM-IV alcoholism/abuse and other psychiatric disorders and the determination of family history of alcoholism were made by psychological autopsy. Specific binding to 5-HT(2A) ((3)H-ketanserin) receptors in the PFC was measured by quantitative autoradiography. RESULTS: 5-HT(2A) binding decreased with age [Brodmann areas (BA) 9, 46 gyrus; r = -0.381, -0.334, p < 0.05]. No differences in receptor binding between alcoholics and controls were detected in the gyrus or sulcus of any PFC area examined. Cases (controls or alcoholics) with a family history of alcoholism (n = 23) had less 5-HT(2A) binding throughout PFC than subjects without (n = 21) a family history of alcoholism (p < 0.05). 5-HT(2A) receptor binding in alcoholics without a family history of alcoholism (n = 7) did not differ from controls without a family history of alcoholism (n = 14). There was no association between alcoholism or alcohol rating and genotype. There was an association between genotype and the total amount of (3)H-ketanserin binding in BA46 with the TT genotype having more binding (TT>TC approximately CC). CONCLUSIONS: Lower 5-HT(2A) receptor binding in the PFC of cases with a family history of alcoholism suggests a genetic predisposition to alcoholism. Alcohol abuse by itself did not have a significant effect on PFC 5-HT(2A) binding and as 5-HT(2A) binding in alcoholics is not different from controls and antagonists may be therapeutic, fewer receptors may result in downstream developmental effects on the brain resulting in a predisposition to alcoholism.