Gaba(A) receptor subunits: their contribution to ethanol and other addictive behaviours in mice

GABAergic neurons play an essential role in pathways signaling both reward, and anxiety. In keeping, human genetic studies have revealed associations between haplotypes of genes encoding individual subunits of GABAA receptors and addictions, especially to alcohol, but also other drugs of abuse. One example is the GABRA2 gene encoding a2 subunits. GABAA receptors expressing a2 subunits are highly expressed in nucleus accumbens, making them potentially important in signaling reward. We have studied the consequences of manipulating the gene encoding a2, on accumbens signalling, and on consumption and self-administration of ethanol. Mice with a2 gene deletion showed a 33% reduction in the amplitude of synaptic GABAA receptor-mediated responses in accumbens medium spiny neurons. In mice with a H101R point mutation in the benzodiazepine binding pocket of a2-containing GABAA receptors, activation of the mutated receptors was facilitated by the atypical benzodiazepine, Ro 15-4513, that in wildtype neurons acted usually to inhibit GABA-induced currents. Consistent with a role for accumbens a2-containing receptors in mediating incentive behaviour, systemic administration of Ro 15- 4513 induced behavioural sensitization in the a2H101R mutant, but not wildtype mice. Nevertheless, a2-/- mice did not differ from wildtype mice in operant self-administration of ethanol/sucrose reinforcers, suggesting a2-containing GABAA receptors are not essential for ethanol reward. Human genetic studies suggest that variations the a2 gene may instead contribute to increased risk of alcoholism by mediating anxiety or stress responses. Consistent with that idea, yohimbine increased selfadministration of ethanol/sucrose mixtures more in a2-/- mice than in wildtype mice. The GABRA2 gene is located on human chromosome 4, close to other GABAA genes encoding a4, b1 and c1 subunits, syntenic with a homologous region on mouse chromosome 5. Human b1 haplotypes have also recently been associated with alcoholism. Heterozygous mice bearing a point mutation of b1subunits, b1L285R that abolishes the ability of mutated receptors to respond to GABA, showed both increased consumption of ethanol in a 2-choice test, and increased instrumental responding for ethanol/sucrose mixtures, despite lower responding for sucrose alone. These observations suggest that GABAA receptors expressing b1, but not those expressing a2 may mediate the incentive properties of ethanol.