PILOT--THE ROLE OF ALLOPREGNANOLONE IN ETHANOL DEPENDENCE

长期暴露于乙醇对整个中皮质边缘系统的GABA-A系统有长期持久的影响。异孕酮是一种神经活性类固醇，是GABA-A受体的有效正调节剂。最近的研究数据清楚地表明，异孕酮的抗惊厥作用和调节GABA-A受体活性的能力在急性乙醇戒断期间得到增强。这些数据表明异孕酮可能在乙醇戒断的急性效应中起重要作用。然而，这些增强的神经行为效应在异孕酮反应的普遍性还没有被检查。此外，这些改变的行为和神经生理效应的持久性尚未得到检验。拟议研究的总体目标是进一步研究急性戒断和长期戒酒期间异孕酮对神经生理和行为敏感性的变化。电生理分析的脑电图（即EEG）和事件相关电位（即erp）记录从皮层，杏仁核和海马体将被用来评估中枢神经系统对异孕酮的神经生理效应的敏感性。运动活动的行为分析将用于评估对异孕酮的行为敏感性的变化。评估皮质、杏仁核和海马体中异孕酮中枢水平的神经化学分析。内源性异孕酮水平将与1)急性乙醇戒断的神经生理和行为措施的严重程度以及2)长期戒断期间个体对异孕酮的神经行为反应有关。假设慢性乙醇暴露增强了急性戒断期间异孕酮对神经行为影响的敏感性。然而，在长时间的禁欲后，对异孕酮的敏感性会减弱。

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.