Mu receptors and ethanol/dopamine interactions

描述（由申请人提供）：有助于控制乙醇饮用行为的神经化学和细胞机制尚未完全了解，但多巴胺参与中脑边缘系统已经假设了一段时间。已知许多神经化学系统调节中脑边缘多巴胺系统的活性，例如，阿片肽及其受体。纳洛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。Mu阿片受体在解剖学上位于腹侧被盖区（VTA），并且已知通过抑制GABA中间神经元来控制VTA多巴胺神经元活性。然而，这一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还没有被确定。我们的初步研究表明，μ阿片受体参与乙醇刺激中脑边缘系统的终端区域之一的腹侧纹状体多巴胺释放的机制。我们建议确定基因缺失或μ阿片受体的不可逆阻断是否会改变腹侧纹状体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同类mu受体敲除和野生型对照，已建立在C57 BL/6背景。这些研究将通过研究纳洛嗪对mu受体的不可逆阻断作用进行补充。我们还将使用两瓶选择程序确定mu受体的缺失或不可逆阻断是否改变乙醇消耗（目的2）。此外，我们建议，以确定是否在腹侧被盖区或腹侧纹状体的μ受体参与的μ受体功能的丧失对乙醇刺激的多巴胺释放的抑制作用（目的3）。这将通过将纳洛嗪显微注射到任一区域并测量乙醇反应来完成。将使用GABA能中间神经元中的细胞和突触活性的电生理学测量来检查μ受体在VTA-多巴胺神经元的控制中的作用（目的4）。这些研究将利用上述遗传学和药理学方法。总之，拟议的实验将阐明μ阿片受体在调节中脑边缘多巴胺活性的乙醇的作用。

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.