The role of GABAA receptors in the acute and chronic effects of ethanol: a decade of progress

Abstract

The past decade has brought many advances in our understanding of GABA A receptor-mediated ethanol action in the central nervous system. We now know that specific GABA A 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 GABA A 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 GABA A 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.

Tobacco smoking interferes with GABA A receptor neuroadaptations during prolonged alcohol withdrawal

“…Extrasynaptic GABA A receptors typically contain alpha 4 and alpha 6 subunits, whereas intrasynaptic GABA A receptors typically contain alpha 1-3 subunits (reviewed in ref. 31). During early phase withdrawal, physiological GABAergic disruptions lead to a transient increase in total numbers of GABA A receptors because extrasynaptic GABA A receptors remain elevated and the synaptic GABA A receptors are being recruited.…”

Novel Therapeutic Strategies for Alcohol and Drug Addiction: Focus on GABA, Ion Channels and Transcranial Magnetic Stimulation

“…GABA is the major inhibitory neurotransmitter in the central nervous system (CNS) and binds GABA A receptors that are a family of chloride ion channels that predominately mediate rapid inhibitory neurotransmission throughout the CNS (Kumar et al, 2009); activation of GABA A receptors by GABA results in an influx of chloride ions, which hyperpolarizes the membrane leading to neuronal inhibition. Moreover, GABA A receptors are heteromeric protein complexes consisting of several homologous membrane-spanning glycoprotein subunits that generate various subunit compositions and may account for variable sensitivity to modulatory drugs such as benzodiazepines, barbiturates, neuroactive steroids, ethanol, and general anesthetics (Olsen and Sieghart, 2009).…”

Ethanol Increases Mechanical Pain Sensitivity in Rats via Activation of GABAA Receptors in Medial Prefrontal Cortex

“…As for the action of ethanol in the central nervous system, some in vitro brain slice studies have shown that ethanol facilitates the release of neurotransmitters such as c-aminobutyric acid (GABA), dopamine, serotonin, and opioids, whereas it inhibits glutamate activity, resulting in alterations in behavior [1]. Ethanol has been shown to be anxiolytic and sedative-hypnotic, as well as impairing cognition and motor coordination, through the enhancement of GABA release [17]. The effects of ethanol on pain perception, however, are controversial.…”