Uhl George R
Molecular Neurobiology Branch, NIDA-IRP, NIH, Box 5180 Baltimore, MD 21224, USA.
Neuropharmacology. 2004;47 Suppl 1:140-7. doi: 10.1016/j.neuropharm.2004.07.029.
Classical genetic studies document strong complex genetic contributions to abuse of multiple addictive substances. These genetic influences are more prominent in the later phases of individuals' progressions toward substance dependence. Individual differences in human addiction vulnerability could thus derive, in part, from individual differences in mnemonic systems. These variations could add to allelic variations that could produce effects on addiction vulnerability phenotypes by other routes that could include (1) differences in drug metabolism or biodistribution, (2) differences in drug's rewarding properties, (3) differences in traits manifest by the addict, including personality differences and (4) differences in the addict's psychiatric comorbidities. Data from linkage and association genome scans now identify chromosomal regions that are likely to contain allelic gene variants that contribute to human addiction vulnerability. Converging positive results are found in several different substance-abusing populations studied in several laboratories. This convergence supports the idea that common allelic variants contribute to individual differences in vulnerability to substance dependence. Genomic markers that identify allelic variants that reproducibly alter addiction vulnerability in several populations provide tools for research in addictions, tools to improve addiction treatments, tools to improve addiction prevention, clues to the genetic bases of individual differences in mnemonic processes and clues to the genetic bases of individual differences in the other traits and disorders that co-occur with substance dependencies.
经典遗传学研究证明，多种成瘾性物质的滥用存在强大的复杂基因影响。这些基因影响在个体发展成物质依赖的后期阶段更为显著。因此，人类成瘾易感性的个体差异可能部分源于记忆系统的个体差异。这些变异可能会增加等位基因变异，而等位基因变异可能通过其他途径对成瘾易感性表型产生影响，这些途径可能包括：（1）药物代谢或生物分布的差异；（2）药物奖赏特性的差异；（3）成瘾者表现出的特质差异，包括人格差异；（4）成瘾者的精神共病差异。连锁和关联基因组扫描数据现已确定了可能包含导致人类成瘾易感性的等位基因变体的染色体区域。在多个实验室研究的几个不同的物质滥用群体中都发现了趋同的阳性结果。这种趋同支持了这样一种观点，即常见的等位基因变体导致了物质依赖易感性的个体差异。能够识别在多个群体中可重复改变成瘾易感性的等位基因变体的基因组标记，为成瘾研究提供了工具，为改善成瘾治疗提供了工具，为加强成瘾预防提供了工具，为记忆过程中个体差异的遗传基础提供了线索，也为与物质依赖同时出现的其他特质和疾病中个体差异的遗传基础提供了线索。
