Alpha4 subunit‐containing GABA_A receptors in the accumbens shell contribute to the reinforcing effects of alcohol

Abstract

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.

Habitual Alcohol Seeking: Neural Bases and Possible Relations to Alcohol Use Disorders

“…However, the ventral striatal region, the NAc, is required for PIT for alcohol cues (Corbit et al, 2016), and this region is also implicated in the direct reinforcing effects of alcohol (Englemann et al 2009; Rewal et al, 2012); it is not clear whether or how dependence upon the NAc for PIT or alcohol reinforcement in may change over time.…”

Ethanol-induced GABAA receptor alpha4 subunit plasticity involves phosphorylation and neuroactive steroids

“…It is unlikely that transient effects from a single exposure contribute to withdrawal effects, as synaptosomal changes occurred when blood ethanol are known to be greater than 300 mg/dL as we have reported elsewhere (see: Carter et al, in press ). GABA A receptor α4 knockout mice displayed normal behavioral responsivity to acute ethanol exposure (Chandra et al, 2008); however, viral-mediated knockdown of α4 subunit levels in the nucleus accumbens shell reveals that α4 expression impacts ethanol operant responding (Rewal et al, 2012). Given that thalamic extrasynaptic α4-containing GABA A receptors mediate tonic inhibitory currents that are potentiated at socially relevant ethanol concentrations (Chandra et al , 2008; Jia et al , 2008), reducing the number of ethanol sensitive receptors is likely a rapid mechanism to ameliorate ethanol’s increased central nervous system inhibition and behavioral responses.…”

Role of GABA-active neurosteroids in the efficacy of metyrapone against cocaine addiction

“…Neurosteroids may also interfere with cocaine-induced associative learning, having important implications for cue-associated reinstatement [72,73]. The latest published research indicates that extrasynaptic GABA A receptors may be especially important in modulating tonic and reward-related dopamine within the mesolimbic circuit [74][75][76][77][78], which supports a role for neurosteroids in these effects since extrasynaptic GABA A receptors are a sensitive target for allopregnanolone and THDOC [75,77,79,80].…”