Extrasynaptic δ-containing GABA _A receptors in the nucleus accumbens dorsomedial shell contribute to alcohol intake

Abstract

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...

Oxytocin prevents ethanol actions at δ subunit-containing GABA A receptors and attenuates ethanol-induced motor impairment in rats

“…The δ-GABA A Rs, sometimes called the "one-glass-of-wine" receptors (24), are located in several brain regions, including the thalamus, cerebellum, hippocampus, and striatum (25,26), and show high sensitivity to relatively low doses of ethanol (2)(3)(4)(5)(6)(7)(8)27). A number of previous studies demonstrate the involvement of δ-GABA A Rs in a range of ethanolinduced functional effects, including ataxia, sedation, and reward (2-8).…”

“…For instance, a genetic polymorphism that exaggerates the actions of ethanol at δ-GABA A Rs also potentiates ethanolinduced motor impairment (2). Further, knockdown of δ subunit expression in the medial shell of the nucleus accumbens reduces alcohol intake in rats (6). Finally, overstimulation and subsequent internalization of α4βδ extrasynaptic GABA A Rs after persistent stimulation by ethanol seem to underlie the development of rapid tolerance to the ataxic effects of ethanol (4).…”

“…The δ-GABA A Rs also represent one of the major targets of ethanol in the CNS, particularly at relatively low ethanol concentrations, and mediate some of the rewarding and ataxic effects of ethanol (2)(3)(4)(5)(6)(7)(8). For instance, a genetic polymorphism that exaggerates the actions of ethanol at δ-GABA A Rs also potentiates ethanolinduced motor impairment (2).…”

Extrasynaptic GABA A receptors in the nucleus accumbens are necessary for alcohol drinking

“…The brain region implicated by Nie et al (1) where extrasynaptic GABA A Rs are critical for EtOH oral intake is the dorsomedial shell of the nucleus accumbens (NAc), an area noted for dopamine-mediated reward mechanisms involved in virtually all drugs of abuse (e.g., cocaine, nicotine, opiates; Fig. 1).…”

“…One particularly important aspect of ethanol (EtOH) is its effect on the reward system in the mammalian brain, because it may help us to understand and help people afflicted with alcohol abuse and addiction better. In PNAS, Patricia Janak, Dorit Ron, and their colleagues (1) at the Ernest Gallo Clinic and Research Center associated with the University of California, San Francisco, are making progress on both aspects by using the technique of viral-mediated RNAi to knock down the expression of a specific inhibitory neurotransmitter receptor protein implicated in low-to moderate-dose EtOH effects on brain. This manipulation was carried out in vivo on rats in a specific mesolimbic brain region implicated in the reinforcing effects of EtOH, producing a significant reduction in oral uptake of EtOH.…”