Opioid Sensitive GABA inputs to the Ventral Midbrain

描述（申请人提供）：Mu-阿片受体广泛分布于中枢和周围神经系统。阿片类药物在中脑边缘多巴胺通路中的作用激活了奖励通路，这是导致滥用和成瘾的多步骤过程中的关键点。阿片受体在中脑边缘系统的多个部分表达，阿片类药物在这一复杂系统的一个区域的作用可能有助于但肯定不会主导阿片类药物有益特性的所有方面。在过去的 20 年里，阿片类药物在腹侧中脑多巴胺系统中的作用依赖于 VTA 的 GABA 中间神经元。抑制这些中间神经元被认为是通过去抑制来增加多巴胺神经元的活性。现在已经清楚，阿片类药物在中脑腹侧的作用更明显。 复杂。有许多 GABA 神经元支配多巴胺神经元，其中许多神经元表达阿片受体。现在可以使用光遗传学工具选择性地操纵这些传入途径中的每一个，从而获得阿片类药物作用的全面图片。该提案将确定首次接受治疗和吗啡治疗的动物中多巴胺神经元对阿片类药物敏感的 GABA 输入。为了使去抑制具有功能相关性，最初必须存在大量的抑制。该假设是抑制的来源取决于动物的状态。每个抑制途径都会 根据动物的行为状态进行不同的招募。拟议的实验将使用脑切片实验来证明不同 GABA 传入通路的相对作用在动物长期吗啡治疗戒断期间发生变化。了解不同的传入途径介导奖赏和退缩将允许采用定向方法来限制奖赏和退缩。

DESCRIPTION (provided by applicant): Mu-opioid receptors are widely distributed in the central and peripheral nervous systems. The action of opioids in the mesolimbic dopamine pathway activates the reward pathway(s) that are a key point in the multistep process leading to abuse and addiction. Opioid receptors are expressed in multiple parts of the mesolimbic system and the action of opioids in one area of this complex system may contribute to, but will surely not dominate all aspects of the rewarding properties of opioids. For the past 20 years the action of opioids in the ventral midbrain dopamine system rested on the GABA interneurons of the VTA. Inhibition of those interneurons was proposed to increase the activity of dopamine neurons through a disinhibition. It is now clear that the action of opioids in the ventral midbrain is more complex. There are a number of GABA neurons that innervate dopamine neurons and many of those neurons express opioid receptors. Each of these afferent pathways can now be manipulated selectively with the use of optogenetic tools such that a comprehensive picture of opioid action can be obtained. This proposal will identify the opioid sensitive GABA inputs to dopamine neurons in naive and morphine treated animals. In order for disinhibition to be functionally relevant, there has to be a substantial amount of inhibition initially. The hypothesisis that the source of inhibition is dependent on the state of the animal. Each inhibitory pathway will be recruited differentially depending on the behavioral state of the animal. The proposed experiments will use brain slice experiments to demonstrate that the relative role of different GABA afferent pathways changes during withdrawal from chronic treatment of animals with morphine. Knowledge that different afferent pathways mediate reward and withdrawal will allow a directed approach to limit both reward and withdrawal.