Mu receptors and ethanol/dopamine interactions

描述(申请人提供)：发展和维持乙醇自我给药的机制还不完全清楚，但多巴胺参与中脑边缘系统的假设已经有一段时间了。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。纳曲酮是临床上用于减少酒精中毒复发的有效药物，是一种广谱阿片受体拮抗剂，但其具体作用机制尚不清楚。MU阿片受体在解剖学上位于腹侧被盖区(VTA)，被认为通过抑制GABA中间神经元来控制VTA多巴胺神经元的活动。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确定。我们的初步研究表明，Mu阿片受体参与了乙醇刺激Long-Evans大鼠伏隔核壳内多巴胺释放的机制。然而，目前尚不清楚Mu阿片受体是否参与了自愿给药前或给药过程中对中脑边缘多巴胺系统的刺激。我们建议确定非选择性阿片受体拮抗剂纳曲酮(Naltrexone)和选择性MU阿片受体拮抗剂β-Funaltrexamine在手术给药过程中对伏隔多巴胺的剂量依赖效应。最后，中脑边缘多巴胺在手术给药过程中的刺激机制可能涉及腹侧被盖区多巴胺神经元放电频率的增加，但这一点尚未在体内测量到。我们建议在目标2中这样做。总之，拟议的实验将有助于在行为相关的背景下阐明Mu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 mechanisms that underlie the development and maintenance of ethanol self-administration 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, for example, the opioid peptides and their receptors. Naltrexone, a clinically effective drug used to reduce relapse in alcoholism, is a broad spectrum opioid receptor antagonist, but its mechanism is not known in detail. Mu opioid receptors are anatomically located in the ventral tegmental area (VTA) and are thought 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 opioid receptor subtypes has not been firmly established. Our preliminary studies show that mu opioid receptors are involved in the mechanism by which ethanol stimulates dopamine release in the shell of the nucleus accumbens in the Long-Evans rat. However, it is still unknown whether mu opioid receptors are involved in the stimulation of mesolimbic dopamine system before or during voluntary ethanol administration. We propose to determine the dose- dependent effects of naltrexone (non-selective opioid receptor antagonist) and beta-funaltrexamine (selective mu opioid receptor antagonist on accumbal dopamine during operant self-administration of ethanol (Aim 1). Finally, the mechanism of the stimulation of mesolimbic dopamine during operant self-administration may involve an increase in the firing rate of dopamine neurons in the ventral tegmental area, but this has not been measured in vivo. We propose to do this in Aim 2. Together, the proposed experiments will help elucidate the role of mu opioid receptors in the modulation of mesolimbic dopamine activity by ethanol in a behaviorally relevant context.