Alpha4 subunit-containing GABA _A receptors in the accumbens shell contribute to the reinforcing effects of alcohol

The α4βδ gamma-aminobutyric acid A receptor (GABA _AR) has been proposed to mediate the rewarding effects of low-to-moderate concentrations of alcohol (ethanol) that approximate those achieved by social drinking. If this is true, then this receptor should be necessary for the reinforcing effects of ethanol as assessed in an instrumental self-administration procedure in which rats are trained to lever press for oral ethanol. We used viral-mediated RNA interference to transiently reduce expression of the α4 GABA _AR subunit in the shell region of the nucleus accumbens (NAc). We found that responding for ethanol was significantly reduced after α4 reductions in the NAc shell, but not NAc core. This reduction was specific to ethanol, as responding for sucrose was not altered. The presence of ethanol was also required as unreinforced responding for ethanol in subjects previously trained to respond for ethanol (i.e. responding during an extinction test) was not altered. In addition, responding during reinforced sessions was not altered during the initial 5 minutes of the session, but decreased after 5 minutes, following multiple reinforced responses. Together, these findings indicate that the α4 GABA _AR subunit in the NAc shell is necessary for the instrumental reinforcing effects of oral ethanol, further supporting a role for α4-containing GABA _ARs in the rewarding/reinforcing effects of ethanol. Possible pharmacological and non-pharmacological explanations for these effects are considered.