Dodd Peter R, Foley Philomena F, Buckley S Tracey, Eckert Allison L, Innes David J
School of Molecular and Microbial Sciences, University of Queensland, Brisbane, Australia.
Addict Behav. 2004 Sep;29(7):1295-309. doi: 10.1016/j.addbeh.2004.06.010.
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.
慢性酒精中毒会导致局部脑损伤，这种损伤在额上叶皮质较为突出，而在运动皮质则较轻。发生酒精依赖的可能性与基因标记有关。酗酒者和对照组之间GABAA受体表达存在差异，而谷氨酸受体的差异则不明显。我们确定基因型是否能区分谷氨酸和γ-氨基丁酸（GABA）受体的局部表达，从而影响酒精所致脑损伤的严重程度。在尸检时从无酒精相关疾病的酗酒者、患有肝硬化的酗酒者以及匹配的对照组获取大脑皮质组织。DRD2A、DRD2B、GABB2、EAAT2和5HTT基因型在N-甲基-D-天冬氨酸（NMDA）受体参数方面并不能区分酗酒病例和对照组。相反，酒精脱氢酶（ADH）3基因型以区域特异性方式与NMDA受体效能和亲和力存在显著相互作用。EAAT2基因型与局部GABAA受体β亚基mRNA表达存在显著相互作用，GABB2和DRD2B基因型与β亚基亚型蛋白表达存在显著相互作用。基因型可能会局部调节氨基酸传递，从而介导神经元的易损性。这对旨在改善脑损伤以及可能改善成瘾的药物干预效果具有重要意义。
