Genes and gene expression in the brain of the alcoholic.
Chronic alcoholism leads to localized brain damage, which is prominent in superior frontal cortex but mild in motor cortex. The likelihood of developing alcohol dependence is associated with genetic markers. GABAA receptor expression differs between alcoholics and controls, whereas glutamate receptor differences are muted. We determined whether genotype differentiated the localized expression of glutamate and gamma-aminobutyric acid (GABA) receptors to influence the severity of alcohol-induced brain damage. Cerebrocortical tissue was obtained at autopsy from alcoholics without alcohol-related disease, alcoholics with cirrhosis, and matched controls. DRD2A, DRD2B, GABB2, EAAT2, and 5HTT genotypes did not divide alcoholic cases and controls on N-methyl-d-aspartate (NMDA) receptor parameters. In contrast, alcohol dehydrogenase (ADH)3 genotype interacted significantly with NMDA receptor efficacy and affinity in a region-specific manner. EAAT2 genotype interacted significantly with local GABAA receptor beta subunit mRNA expression, and GABB2 and DRD2B genotypes with beta subunit isoform protein expression. Genotype may modulate amino acid transmission locally so as to mediate neuronal vulnerability. This has implications for the effectiveness of pharmacological interventions aimed at ameliorating brain damage and, possibly, dependence.
Dodd
Peter R
PR
School of Molecular and Microbial Sciences, University of Queensland, Brisbane, Australia. p.dodd@uq.edu.au
Foley
Philomena F
PF
Buckley
S Tracey
ST
Eckert
Allison L
AL
Innes
David J
DJ
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000426:Alcohol Dehydrogenase / Q000235:genetics / Q000378:metabolism; D000437:Alcoholism / Q000235:genetics* / Q000378:metabolism; D000596:Amino Acids / Q000378:metabolism; D000704:Analysis of Variance; D001921:Brain / Q000378:metabolism*; D016022:Case-Control Studies; D005260:Female; D015870:Gene Expression; D005838:Genotype; D006801:Humans; D008104:Liver Cirrhosis, Alcoholic / Q000235:genetics / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D018377:Neurotransmitter Agents / Q000378:metabolism*; D011485:Protein Binding; D020033:Protein Isoforms / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D011963:Receptors, GABA-A / Q000235:genetics; D017470:Receptors, Glutamate / Q000235:genetics; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
D000596:Amino Acids; D018377:Neurotransmitter Agents; D020033:Protein Isoforms; D012333:RNA, Messenger; D011963:Receptors, GABA-A; D017470:Receptors, Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; D000426:Alcohol Dehydrogenase