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

Ernest Gallo Clinic and Research Center, University of California at San Francisco, 5858 Horton Street, Emeryville, CA 94608, USA.
Addiction Biology (Impact Factor: 5.36). 04/2011; 17(2):309-21. DOI: 10.1111/j.1369-1600.2011.00333.x
Source: PubMed


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

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    • "Voluntary EtOH (6%, equal 1 g/kg, ∼13 mmol/L) consumption induced an elevation of dopamine in the rat mesolimbic reward pathway74. Using viral-mediated RNA interference to transiently reduce α4-containing GABAARs in the shell region of the NAc could reduce self-administration of EtOH intake75. Blockade of GABAARs in the para-ventricular nucleus of the hypothalamus, which is the main integration site controlling the hypothalamic-pituitary-adrenal (HPA) neuroendocrine stress system, could reduce voluntary EtOH drinking76. "
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    • "The GABA A receptor/ chloride channel complex is a pentameric ligand-gated ion channel and the major inhibitory neurotransmitter receptor in the mammalian brain. Several subunits have been identified, with the majority of GABA A receptors composed of α, β, γ and δ subunits (Barnard et al., 1998; Rewal et al., 2012). Using different receptor constructs, putative ethanol binding sites in the transmembrane domaines of the α/ β subunits of the GABA A receptor have been identified (Mihic et al., 1997), and genetic variants within the genes encoding these subunits have been shown to affect the vulnerability to alcohol dependence (Cui et al., 2012; Frank et al., 2012; Uhart et al., 2012). "
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