Neurosteroid Modulation of Ethanol Intake and Reward

描述（由申请人提供）：拟议研究的目标是描述神经甾体别孕烯醇酮（ALLOP）在腹侧被盖区（VTA）水平对乙醇自我给药模式和大脑奖励通路激活的机制作用。VTA中的γ-氨基丁酸A型（GABA-A）受体被认为部分介导了乙醇的主观和动机效应;推测是通过调节从VTA到延髓核（NAc）的中脑边缘多巴胺能投射。神经类固醇ALLOP是GABA-A受体的内源性正调节剂，已被证明可增强对乙醇的维持和恢复操作性反应以及增强乙醇自我给药。第一个具体目标将确定操纵VTA内ALLOP的水平和代谢（磺化）对小鼠中已建立的乙醇消耗模式的影响。第二个研究目标的研究将评估VTA应用ALLOP对NAc DA的影响，并将评估ALLOP与乙醇刺激的细胞外NAc DA水平变化的相互作用。这些实验的结果将为神经类固醇调节乙醇摄入和奖励的机制提供有价值的见解。

DESCRIPTION (provided by applicant): The goal of the proposed research is to delineate a mechanistic role for the neurosteroid allopregnanolone (ALLOP) at the level of the ventral tegmental area (VTA) on ethanol self-administration patterns and brain reward pathway activation. Gamma-aminobutyric acid type A (GABA-A) receptors in the VTA are thought to mediate, in part, ethanol's subjective and motivational effects; presumably via modulation of the mesolimbic dopaminergic projection from the VTA to the nucleus accumbens (NAc). The neurosteroid ALLOP, an endogenous positive modulator of GABA-A receptors, has been demonstrated to potentiate maintained and reinstated operant responding for ethanol as well as augment ethanol self-administration. The first specific aim will determine the effects of manipulating the levels and metabolism (sulfonation) of ALLOP within the VTA on established ethanol consumption patterns in mice. Studies in the second research aim will assess the impact of VTA-applied ALLOP on NAc DA and will evaluate ALLOP's interaction with ethanol-stimulated changes in extracellular NAc DA levels. Results from these experiments will provide valuable insights into the mechanisms underlying neurosteroid modulation of ethanol intake and reward.