concentrations. However, it has been shown that increasing the ambient extracellular GABA concentration results in tonic activation of gamma2 subunit-containing GABAA extrasynaptic receptors [44], [45]. This could be one explanation for the up-regulation of GABRG2 and GPHN in alcohol naïve P rats that, as mentioned earlier, may have chronically increased GABA levels in the synaptic cleft relative to NP rats. In contrast, the down-regulation of GABRG2 (and GPHN) in alcoholics and cocaine addicts might be compensatory and a feature of tolerance to drug. This is supported by preclinical findings; for example cynomolgus macaque monkeys allowed to self-administer ethanol for 18 months show reduced gamma2 mRNA expression in the amygdala [46] and cultured rat hippocampal neurons exposed to ethanol for 5 days likewise showed reduced gamma2 mRNA levels [47].
