Family history of alcoholism is associated with lower 5-HT2A receptor binding in the prefrontal cortex

Background: 5-Hydroxytryptophan (5-HT2A) receptor involvement in alcoholism is suggested by less 5-HT2A binding in alcohol preferring rats, association of a 5-HT2A receptor gene polymorphism with alcohol dependence and reduced alcohol intake with 5-HT2A antagonists. We sought to determine postmortem whether 5-HT2A 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-HT2A (H-3-ketanserin) receptors in the PFC was measured by quantitative autoradiography. Results: 5-HT2A 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-HT2A binding throughout PFC than subjects without (n = 21) a family history of alcoholism (p < 0.05). 5-HT2A 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 H-3-ketanserin binding in BA46 with the TT genotype having more binding (TT > TC approximate to CC). Conclusions: Lower 5-HT2A 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-HT2A binding and as 5-HT2A 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.