PILOT--THE ROLE OF ALLOPREGNANOLONE IN ETHANOL DEPENDENCE

长期接触乙醇会对整个皮质边缘系统的GABA-A系统产生长期的影响。别孕酮是一种神经活性类固醇，对GABA-A受体具有很强的正向调节作用。最近研究的数据清楚地表明，在急性酒精戒断过程中，别孕酮的抗惊厥作用和调节GABA-A受体活性的能力增强。这些数据表明，别孕酮可能在乙醇戒断的急性效应中发挥重要作用。然而，这些对别孕酮反应增强的神经行为效应的普遍性还没有被研究过。此外，这些改变的行为和神经生理效应的持久性还没有得到检验。拟议研究的总体目标是进一步检测急性戒断和长期戒酒期间对别孕酮的神经生理和行为敏感性的变化。对大脑皮质、杏仁核和海马区记录的脑电(即脑电)和事件相关电位(即事件相关电位)进行电生理学分析，以评估中枢神经系统对别孕酮的神经生理作用的敏感性。运动活动的行为分析将用于评估对别孕酮的行为敏感性的变化。神经化学分析，评估皮质、杏仁核和海马区别孕酮的中枢水平。内源性别孕酮水平将与1)急性酒精戒断的神经生理和行为指标的严重程度有关，以及2)在长期戒断期间个体对别孕酮的神经行为反应。假设在急性戒断过程中，慢性酒精暴露会增强对别孕酮神经行为影响的敏感性。然而，在长期戒断之后，对别孕酮的敏感性将会减弱。

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.