Genetic factors in addiction: QTL mapping and candidate gene studies implicate GABAergic genes in alcohol and barbiturate withdrawal in mice.

Quantitative trait locus (QTL) mapping has allowed dramatic progress toward the detection and chromosome mapping of minor and major gene loci involved in murine responses to alcohol and other drugs of abuse. Here we focus on the identification of QTLs for one particular trait relevant to addiction, drug withdrawal following acute or chronic drug administration. To date, five significant QTLs (p < 5 x 10(-5)) and six suggestive QTLs (p < 0.001) have been mapped to specific murine chromosomes for alcohol and pentobarbital withdrawal, indicating the presence of a relevant gene or genes at each location. Overlapping QTLs for alcohol withdrawal and pentobarbital withdrawal are identified on murine chromosomes 1, 4, and 11, and may detect the influence of common genes. For many QTLs, candidate genes with relevant neurobiological function lie within the mapped region. Notably, several QTLs for alcohol and pentobarbital withdrawal are in proximity to genes that directly or indirectly affect GABAA receptor-mediated transmission, which has been implicated in some of the actions of alcohol and other drugs. These include a cluster of GABAA receptor genes and genes encoding the enzymes steroid 5 alpha-reductase-1 (involved in biosynthesis of the neuroactive steroid allopregnanolone) and glutamic acid decarboxylase-1 (involved in GABA biosynthesis). This paper will discuss data that examines the involvement of GABAergic genes in withdrawal and other drug responses, including genetic variation in gene sequence, expression and function.