Overall GABA transmission may be reduced because the upstream regulator analysis (Table 5) identified bicuculine, a GABAA antagonist, as being capable of producing some of the changes seen with ethanol. Changes in GABAA subunit expression may therefore be compensatory for this loss. One of the main aspects of GABAA receptors in the PAG is tonic inhibition (Behbehani, 1995). GABAA receptors composed of Gabrd along with the α4 or α6 subunit are primarily found extrasynaptically (Lovinger and Roberto, 2013); these receptors generate tonic inhibitory conductance (Hanchar et al., 2005). These extra synaptic receptors are sensitive to ethanol, which potentiates this tonic current in a protein kinase C delta dependent manner (Lovinger and Roberto, 2013). Given this potentiation, it is notable that Gabrd and Gabra6, both highly expressed, were both increased along with Prkcd. The most highly expressed GABA transporter (Slc6a11, GAT2) was decreased, which could leave more GABA in extracellular spaces, where it could activate phasic or tonic GABA conductance. Three of the genes downstream of bicuculine (Ier2, Cyr61 and Dusp1) were increased in the other 3 brain regions studied (McBride et al., 2014, McClintick et al., 2015).
