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A Conceptualization of Integrated Actions of Ethanol Contributing to it's GABAMimetic Profile: A Com

A Conceptualization of Integrated Actions of Ethanol Contributing to it's GABAMimetic Profile: A Com

  1. Jatelka
    Neuropsychopharmacology (2005) 30, 1407–1425

    Hugh E Criswell, and George R Breese

    Early behavioral investigations supported the contention that systemic ethanol displays a GABAmimetic profile. Microinjection of GABA
    agonists into brain and in vivo electrophysiological studies implicated a regionally specific action of ethanol on GABA function. While selectivity of ethanol to enhance the effect of GABA was initially attributed an effect on type-1-benzodiazepine (BZD)-GABAA receptors, a lack of ethanol’s effect on GABA responsiveness from isolated neurons with this receptor subtype discounted this contention. Nonetheless, subsequent work identified GABAA receptor subtypes, with limited distribution in brain, sensitive to enhancement of GABA at relevant ethanol concentrations. In view of these data, it is hypothesized that the GABAmimetic profile for
    ethanol is due to activation of mechanisms associated with GABA function, distinct from a direct action on the majority of postsynaptic
    GABA A receptors. The primary action proposed to account for ethanol’s regional specificity on GABA transmission is its ability to release GABA from some, but not all, presynaptic GABAergic terminals. As systemic administration of ethanol increases neuroactive steroids, which can enhance GABA responsiveness, this elevated level of neurosteroids is proposed to magnify the effect of GABA released by ethanol. Additional factors contributing to the degree to which ethanol interacts with GABA function include an involvement of GABA B and other receptors that influence ethanol-induced GABA release, an effect of phosphorylation on GABA responsiveness, and a regional reduction of glutamatergic tone. Thus, an integration of these consequences induced by ethanol is proposed to provide a logical basis for
    its in vivo GABAmimetic profile