The second robust finding that was common to alcoholics, cocaine addicts and P rats was altered expression of GABRG2 and also GPHN (encoding gephryin). GABRG2 encodes the gamma2 subunit, a component of approximately 75% of all neuronal GABAA receptors that is essential for benzodiazepine sensitivity [38]. The gamma2 subunit is required for synaptic clustering of GABAA receptors and for the recruitment to postsynaptic sites of gephryin, a scaffolding protein that anchors GABAA receptors to the postsynaptic skeleton [39]–[43]. Both GABRG2 and GPHN were significantly up-regulated in alcohol-naïve P rats relative to NP rats. In contrast, GABRG2 was significantly down-regulated in alcoholics and cocaine addicts relative to controls and likewise GPHN was down-regulated in cocaine addicts. Under normal circumstances, only GABAA receptors that include a delta subunit in place of a gamma2 subunit are responsive to the usually low extrasynaptic GABA 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
