Mu receptors and ethanol/dopamine interactions

描述（由申请人提供）：控制酒精饮酒行为的神经化学和细胞机制尚不完全清楚，但多巴胺在中脑边缘系统中的参与已经被假设了一段时间。已知许多神经化学系统调节中边缘多巴胺系统的活性，例如阿片肽及其受体。纳曲酮是一种广谱阿片受体拮抗剂，临床上用于减少酒精中毒复发的有效药物，但其作用机制尚不清楚。阿片受体位于腹侧被盖区（VTA），通过抑制GABA中间神经元来控制VTA多巴胺神经元的活性。然而，这种机制在乙醇调节多巴胺释放中的作用，以及特定阿片受体亚型的作用尚未确定。我们的初步研究表明，多巴胺受体参与了乙醇刺激腹侧纹状体释放多巴胺的机制，腹侧纹状体是中脑边缘系统的终端区域之一。我们打算确定阿片受体的基因缺失或不可逆阻断是否会改变腹侧纹状体中乙醇刺激多巴胺释放的剂量-反应曲线（目的1）。我们建议使用的遗传模型将是在C57BL/6背景下建立的同源mu受体敲除和野生型对照。这些研究将通过使用纳洛唑嗪对mu受体进行不可逆阻断的研究来补充。我们还将使用两瓶选择程序确定mu受体的删除或不可逆阻断是否会改变乙醇消耗（目的2）。此外，我们建议确定是否在腹侧被盖区或腹侧纹状体的mu受体参与了mu受体功能丧失对乙醇刺激的多巴胺释放的抑制作用（目的3）。这将通过向任一区域微量注射纳洛唑嗪并测量乙醇反应来完成。mu受体在vta -多巴胺神经元控制中的作用将通过电生理测量gaba能中间神经元的细胞和突触活动来检验（目的4）。这些研究将利用上述遗传和药理学方法。综上所述，本实验将阐明阿片受体在乙醇调节中脑边缘多巴胺活性中的作用。

DESCRIPTION (provided by applicant): The neurochemical and cellular mechanisms that contribute to the control of ethanol drinking behavior are not fully understood, but the involvement of dopamine in the mesolimbic system has been hypothesized for some time. Many neurochemical systems are known to regulate the activity of the mesolimbic dopamine system, e.g., the opiate peptides and their receptors. Naltrexone, a clinically effective drug used to reduce relapse in alcoholism, is a broad spectrum opiate receptor antagonist, but its mechanism is not known in detail. Mu opiate receptors are anatomically located in the ventral tegmental area (VTA) and are known to control VTA dopamine neuron activity through the inhibition of GABA interneurons. However, the role of this mechanism in ethanol's regulation of dopamine release, and the role of particular opiate receptor subtypes has not been firmly established. Our preliminary studies show that mu opiate receptors are involved in the mechanism by which ethanol stimulates dopamine release in the ventral striatum, one of the terminal areas of the mesolimbic system. We propose to determine whether genetic deletion or irreversible blockade of the mu opiate receptor alters the dose-response curve for ethanol-stimulated dopamine release in the ventral striatum (aim 1). The genetic model we propose to use will be congenic mu receptor knockouts and wild-type controls that have been established on a C57BL/6 background. These studies will be complemented by investigation of effects of irreversible blockade of mu receptors with the use of naloxonazine. We also will determine whether the deletion of the mu receptor or irreversible blockade alters ethanol consumption using a two bottle choice procedure (aim 2). Moreover, we propose to determine whether mu receptors in the ventral tegmental area or the ventral striatum are involved in the inhibitory effects of loss of mu receptor function on ethanol stimulated dopamine release (aim 3). This will be done by microinjection of naloxonazine into either area and measuring the ethanol response. The role of mu receptors in the control of VTA-dopamine neurons will be examined using electrophysiological measures of cellular and synaptic activity in GABAergic interneurons (aim 4). These studies will utilize both the genetic and pharmacological approaches as described above. Together, the proposed experiments will elucidate the role of mu opiate receptors in the modulation of mesolimbic dopamine activity by ethanol.