Genetic modulation of amino acid transmitter receptor subunit expression in alcoholic human brain

Alcoholics differ in craving, severity of withdrawal, propensity for dependence and degree of brain damage. There is a strong genetic component: the heritability of dependence is estimated to be 50–60%. Genetic control of neurotransmitter receptor subunit composition in the brain may contribute to liability to alcohol dependence etc. Identification of relevant polymorphisms will help guide development of more precisely targeted treatment. We investigated genotype-phenotype interactions in GABA-A and glutamate-NMDA receptor subunit expression in autopsy tissue extracts from alcoholics with and without cirrhosis, and matched controls. Samples were of superior frontal cortex (vulnerable to alcoholic pathology) and primary motor cortex (spared). We genotyped a range of markers reportedly associated with alcohol misuse and dependence.Subunit mRNA transcript expression was quantified by RealTime RT PCR, subunit protein expression by immunoblotting;receptor pharmacology was assessed by binding assays. Few of the genotypes modulated receptor subunit expression and density. GABRB2 and 5HTTLPR genotypes mediated glutamate- NMDA receptor expression, notably in cirrhotic alcoholics and females. There were significant, regionally selective, interactions of DRD2, SLC1A2 and APOE genotypes with GABA-A receptor beta-subunit expression in alcoholics without comorbid disease. In each instance, possession of the alcoholism-associated allele was associated with altered expression in a manner likely to promote local excitotoxicity. Subunit composition controls receptor pharmacology, so subjects may be at greater risk of alcohol-induced brain damage as a consequence of their genetic make-up