Recent findings suggest that extrasynaptic δ-subunit-containing GABA A receptors are sensitive to low-to-moderate concentrations of alcohol, raising the possibility that these receptors mediate the reinforcing effects of alcohol after consumption of one or a few drinks. We used the technique of viral-mediated RNAi to reduce expression of the GABA A receptor δ-subunit in adult rats in localized regions of the nucleus accumbens (NAc) to test the hypothesis that δ-subunit-containing GABA A receptors in the NAc are necessary for oral alcohol consumption. We found that knockdown of the δ-subunit in the medial shell region of the NAc, but not in the ventral or lateral shell or in the core, reduced alcohol intake. In contrast, δ-subunit knockdown in the medial shell did not affect intake of a 2% sucrose solution, suggesting that the effects of GABA A receptor δ-subunit reduction are specific to alcohol. These results provide strong evidence that extrasynaptic δ-subunitcontaining GABA A receptors in the medial shell of the NAc are critical for the reinforcing effects of oral ethanol. 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP) enhances the acquisition of alcohol consumption in laboratory rats (6), whereas the opposite effect, a reduction of alcohol self-administration, is observed after administration of the GABA A R antagonists Ro15-4513 or picrotoxin (7-9).GABA A Rs are pentamers assembled from a variety of subunits to form multiple isoforms that are likely to differ in their alcohol sensitivity (10). Although many GABA A R subunit combinations can be activated by high (anesthetic) alcohol concentrations (11), only specific GABA A R subunit combinations, specifically those containing a δ-subunit, appear to be sensitive to alcohol concentrations in the lower range of blood alcohol levels associated with mild to moderate intoxication in humans (12-15). For example, recombinant α 4 βδ and α 6 βδ GABA A Rs are reported to be sensitive to 3-30 mM concentrations of alcohol (12,14,16). Interestingly, δ-subunit-containing GABA A Rs are exclusively located at extrasynaptic locations (17-19), where they give rise to a tonic form of inhibition that potently suppresses neuronal excitability. A number of studies have shown that alcohol at low concentrations acts through extrasynaptic δ-containing GABA A Rs to increase tonic inhibition (20-24).The above findings suggest that actions at extrasynaptic δ-containing GABA A Rs could be critical for a variety of cognitive and behavioral effects of consumed alcohol, including anxiolysis, behavioral tolerance, and rewarding and reinforcing effects. However, δ-subunit knockout mice, and the related α 4 -subunit knockout mice, demonstrate relatively few alterations in the effects of alcohol in vivo. For example, the effects of acute alcohol administration on measures of anxiety, hypothermia, and sedation are not altered in these mice (25,26). In contrast, δ-subunit knockout mice drink less than their wild-type counterparts (25).Thus, δ-containing receptors may be involved in rewar...

Alcohol has subjective and behavioral effects at the pharmacological levels typically reached during the consumption of one or two alcoholic drinks. Here we provide evidence that an ␣4-subunit-containing GABA A receptor contributes to the consumption of low-tomoderate levels of alcohol. Using viral-mediated RNA interference (RNAi), we found that reduced expression of the ␣4 subunit in the nucleus accumbens (NAc) shell of rats decreased their free consumption of and preference for alcohol. The time course for the reduced alcohol intake paralleled the time course of ␣4 mRNA reductions achieved after viral-mediated RNAi for ␣4. Furthermore, the reduction in drinking was region-and alcohol-specific: there was no effect of reductions in ␣4 expression in the NAc core on alcohol intake, and reductions in ␣4 expression in the NAc shell did not alter sucrose or water intake. These results indicate that the GABA A receptor ␣4 subunit in the NAc shell mediates alcohol intake.

The α4βδ gamma-aminobutyric acid A receptor (GABAAR) 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 GABAAR 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 GABAAR subunit in the NAc shell is necessary for the instrumental reinforcing effects of oral ethanol, further supporting a role for α4-containing GABAARs in the rewarding/reinforcing effects of ethanol. Possible pharmacological and non-pharmacological explanations for these effects are considered.

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