Allelic Association of the D2 Dopamine Receptor Gene With Receptor-Binding Characteristics in Alcoholism or Gene ism

TLDR

The study genotyped D₂ receptor alleles by digesting cortical DNA with Taql and probing a 1.5‑kb clone, then measured receptor binding affinity (K_d) and density (B_max) in caudate nuclei using tritiated spiperone. Alcoholic brains exhibited significantly lower K_d and reduced B_max, especially in A1 allele carriers, with a gradient of B_max across genotypes, suggesting that D₂ receptor polymorphism may contribute to severe alcoholism susceptibility.

Abstract

• The allelic association of the human D₂dopamine receptor gene with the binding characteristics of the D₂dopamine receptor was determined in 66 brains of alcoholic and nonalcoholic subjects. In a blinded experiment, DNA from the cerebral cortex was treated with the restriction endonuclease Taql and probed with a 1.5-kilobase (kb) digest of a clone (XhD2G1) of the human D₂dopamine receptor gene. The binding characteristics (K_d[binding affinity] and B_max[number of binding sites]) of the D₂dopamine receptor were determined in the caudate nuclei of these brains using tritiated spiperone as the ligand. The adjusted K_dwas significantly lower in alcoholic than in nonalcoholic subjects. In subjects with the A1 allele, in whom a high association with alcoholism was found, the B_maxwas significantly reduced compared with the B_maxof subjects with the A2 allele. Moreover, a progressively reduced B_maxwas found in subjects with A2/A2, A1/A2, and A1/A1 alleles, with subjects with A2/A2 having the highest mean values, and subjects with A1/A1, the lowest. The polymorphic pattern of the D₂dopamine receptor gene and its differential expression of receptors suggests the involvement of the dopaminergic system in conferring susceptibility to at least one subtype of severe alcoholism.