https://www.cell.com/neuron/pdf/S0896-6273(11)01093-2.pdf

Extrasynaptic GABAA receptors: Their function in the CNS and implications for disease

How addictive drugs disrupt presynaptic dopamine neurotransmission.

The past decade has brought many advances in our understanding of GABAA receptor-mediated ethanol action in the central nervous system. We now know that specific GABAA receptor subtypes are sensitive to ethanol at doses attained during social drinking while other subtypes respond to ethanol at doses attained by severe intoxication. Furthermore, ethanol increases GABAergic neurotransmission through indirect effects, including the elevation of endogenous GABAergic neuroactive steroids, presynaptic release of GABA, and dephosphorylation of GABAA receptors promoting increases in GABA sensitivity. Ethanol’s effects on intracellular signaling also influence GABAergic transmission in multiple ways that vary across brain regions and cell types. The effects of chronic ethanol administration are influenced by adaptations in GABAA receptor function, expression, trafficking, and subcellular localization that contribute to ethanol tolerance, dependence, and withdrawal hyperexcitability. Adolescents exhibit altered sensitivity to ethanol actions, the tendency for higher drinking and longer lasting GABAergic adaptations to chronic ethanol administration. The elucidation of the mechanisms that underlie adaptations to ethanol exposure are leading to a better understanding of the regulation of inhibitory transmission and new targets for therapies to support recovery from ethanol withdrawal and alcoholism.

/pdf/the-role-of-gaba-a-receptors-in-the-acute-and-chronic-4zyeeaz5uz.pdf

The role of GABA(A) receptors in the acute and chronic effects of ethanol: a decade of progress.

Chronic alcohol neuroadaptation and stress contribute to susceptibility for alcohol craving and relapse.

An Emerging Circuit Pharmacology of GABAA Receptors.

Recent findings suggest that extrasynaptic δ-subunit–containing GABAA 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 GABAA receptor δ-subunit in adult rats in localized regions of the nucleus accumbens (NAc) to test the hypothesis that δ-subunit–containing GABAA 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 GABAA receptor δ-subunit reduction are specific to alcohol. These results provide strong evidence that extrasynaptic δ-subunit–containing GABAA receptors in the medial shell of the NAc are critical for the reinforcing effects of oral ethanol.

https://www.pnas.org/content/pnas/108/11/4459.full.pdf

Extrasynaptic delta-containing GABAA receptors in the nucleus accumbens dorsomedial shell contribute to 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.

/pdf/alpha4-subunit-containing-gabaa-receptors-in-the-accumbens-b4mz5sdgtu.pdf

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

Sliding Doors: The Ethics of Patient Preferences for Providers from Different Backgrounds (Sci254)

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 alpha4-subunit-containing GABA(A) receptor contributes to the consumption of low-to-moderate levels of alcohol. Using viral-mediated RNA interference (RNAi), we found that reduced expression of the alpha4 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 alpha4 mRNA reductions achieved after viral-mediated RNAi for alpha4. Furthermore, the reduction in drinking was region- and alcohol-specific: there was no effect of reductions in alpha4 expression in the NAc core on alcohol intake, and reductions in alpha4 expression in the NAc shell did not alter sucrose or water intake. These results indicate that the GABA(A) receptor alpha4 subunit in the NAc shell mediates alcohol intake.

https://www.jneurosci.org/content/jneuro/29/2/543.full.pdf

α4-Containing GABAA Receptors in the Nucleus Accumbens Mediate Moderate Intake of Alcohol

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Extrasynaptic delta-containing GABAA receptors in the nucleus accumbens dorsomedial shell contribute to alcohol intake.

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

Sliding Doors: The Ethics of Patient Preferences for Providers from Different Backgrounds (Sci254)

α4-Containing GABAA Receptors in the Nucleus Accumbens Mediate Moderate Intake of Alcohol