Chronic exposure to ethanol has long lasting effects on GABA-A system throughout the mesocorticolimbic system. Allopregnanolone is a neuroactive steroid which functions as a potent positive modulator of GABA-A receptors. Data from recent studies clearly demonstrate that allopregnanolone's anticonvulsant effects and ability to modulate GABA-A receptor activity are enhanced during acute ethanol withdrawal. These data suggest that allopregnanolone may play an important role in the acute effects of ethanol withdrawal. However, the generality of these enhanced nurobehavioral effects in response to allopregnanolone have not been examined. Further, the persistence of these altered behavioral and neurophysiological effects has not been examined. The overall goal of the proposed studies is to further examine changes in the neurophysiological and behavioral sensitivity to allopregnanolone during acute withdrawal and protracted abstinence from ethanol. Electrophysiological analyses of the electroencephalogram (i.e. EEG) and event-related potentials (i.e. ERPs) recorded from the cortex, amygdala and hippocampus will be used to assess the sensitivity of the central nervous system to allopregnanolone's neurophysiological effects. Behavioral analysis of locomotor activity will be used to assess changes in the behavioral sensitivity to allopregnanolone. Neurochemical analyses which assesses central levels of allopregnanolone in the cortex, amygdala and hippocampus. Endogenous allopregnanolone levels will then be related to 1) the severity of neurophysiological and behavioral measures of acute ethanol withdrawal and 2) to individual neurobehavioral responsivity to allopregnanolone during protracted abstinence. It is hypothesized that chronic ethanol exposure enhances sensitivity to the neurobehavioral effects of allopregnanolone during acute withdrawal. However, after prolonged periods of abstinence sensitivity to allopregnanolone will be blunted.
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