Dynamic c-Fos changes in mouse brain during acute and protracted withdrawal from chronic intermittent ethanol exposure and relapse drinking.
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Alcohol dependence promotes neuroadaptations in numerous brain areas, leading to escalated drinking and enhanced relapse vulnerability. We previously developed a mouse model of ethanol dependence and relapse drinking in which repeated cycles of chronic intermittent ethanol (CIE) vapor exposure drive a significant escalation of voluntary ethanol drinking. In the current study, we used this model to evaluate changes in neuronal activity (as indexed by c-Fos expression) throughout acute and protracted withdrawal from CIE (combined with or without a history of ethanol drinking). We analyzed c-Fos protein expression in 29 brain regions in mice sacrificed 2, 10, 26, and 74hours or 7days after withdrawal from 5cycles of CIE. Results revealed dynamic time- and brain region-dependent changes in c-Fos activity over the time course of withdrawal from CIE exposure, as compared with nondependent air-exposed control mice, beginning with markedly low expression levels upon removal from the ethanol vapor chambers (2hours), reflecting intoxication. c-Fos expression was enhanced during acute CIE withdrawal (10 and 26hours), followed by widespread reductions at the beginning of protracted withdrawal (74hours) in several brain areas. Persistent reductions in c-Fos expression were observed during prolonged withdrawal (7days) in prelimbic cortex, nucleus accumbens shell, dorsomedial striatum, paraventricular nucleus of thalamus, and ventral subiculum. A history of ethanol drinking altered acute CIE withdrawal effects and caused widespread reductions in c-Fos that persisted during extended abstinence even without CIE exposure. These data indicate that ethanol dependence and relapse drinking drive long-lasting neuroadaptations in several brain regions.
author list (cited authors)
Smith, R. J., Anderson, R. I., Haun, H. L., Mulholland, P. J., Griffin, W. C., Lopez, M. F., & Becker, H. C.