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Anxiety is a motivational component for many drugs of abuse, including ethanol. For example, acute ethanol reduces behavioral anxiety. This acute anxiolysis may be an underlying mechanism responsible for the co-morbidity1 and familial segregation2 of anxiety disorders and alcoholism. This anxiety-alcohol interaction is also represented during the withdrawal from chronic ethanol exposure that dramatically increases anxiety presumably due to adaptations in neurotransmitter systems governing this behavior. Indeed, increased anxiety is a common cause of relapse in abstinent alcoholics.3 Unfortunately, the neural basis for the relationship between ethanol-anxiety is not well understood. However, measures of heightened neuronal activity during ethanol withdrawal appear in the sensory, memory, and cognitive pathways regulating anxiety.4-6 To identify the cellular and molecular mechanisms regulating these relationships, we explored the functional adaptations to chronic ethanol ingestion using well-established liquid diet models7, 8 and whole cell patch clamp measures in acutely isolated lateral/basolateral amygdala neurons.
We have specifically examined GABAA and strychnine-sensitive glycine receptors since manipulation of amygdala ligand-gated chloride channels can directly influence anxiety.9 GABA-mediated currents and current densities were significantly larger in neurons derived from animals that ingested chronic ethanol compared to cells from control liquid diet rats. Conversely, the magnitude of both glycine-mediated currents and glycine current densities did not vary significantly from control, suggesting that the chronic ethanol-induced alterations in lateral/basolateral amygdala ligand-gated chloride channels were specific for GABAA receptors. Importantly, chronic ethanol exposure altered neither acute benzodiazepine efficacy nor acute ethanol sensitivity. During these studies, we noticed that the effects of acute ethanol on GABAA responses from both control and chronic ethanol-exposed were modestly inhibitory. We explored the inhibitory actions of ethanol on lateral/basolateral amygdala GABAA receptors by investigating the role of subunit composition in these acute effects. Specifically, we expressed GABAA receptors composed of subunits that are highly expressed in the lateral/basolateral amygdala, namely α1, α2, β2, and γ2S.10, 11 Indeed, GABA currents mediated by α2β2γ2S receptors were modestly inhibited by acute ethanol (100mM) while those containing the α1β2γ2S subunits were modestly facilitated. These findings suggest that subunit composition may indeed influence the acute effects of ethanol on lateral/basolateral amygdala GABAA receptors and ultimately determine their adaptive response to chronic ethanol exposure. Furthermore, the acute inhibition of amygdala GABAA receptors by ethanol make it unlikely that direct action on this particular receptor system mediates the acute anxiolytic effects of ethanol. Conversely, the facilitation of GABAA receptor function during chronic ethanol may be one mechanism by which ethanol maintains it’s anxiolytic potential during prolonged exposures.
This work was supported by NIAAA and a pilot grant from Texas A&M University Center for Environmental and Rural Health (BAM).