Opioid sensitive GABA outputs from the nucleus accumbens

 描述(申请人提供)：吗啡是治疗短期中度到重度疼痛的首选药物。然而，长期使用往往会导致耐受性的发展和最终的依赖。这些表型的神经机制尚不完全清楚。很明显，吗啡作用于大脑中的阿片受体，导致含有阿片受体的神经元受到抑制。在中脑，激动剂与GABA神经元上的阿片受体结合导致多巴胺(DA)神经元的去抑制。由此产生的DA释放的增加被认为有助于阿片类药物的回报和成瘾方面。最近的证据表明，中脑DA神经元有几个对阿片敏感的GABA输入。其中一种GABA能投射来自伏核(NAC)的中棘神经元(MSN)，并投射到腹侧被盖区(VTA)。初步结果表明，表达D_1和D_2DA受体的MSN均投射到VTA。这两组神经元表达不同的阿片受体(分别为Kappa和Mu)，并与不同的靶神经元突触。此外，NAC投射同时针对VTA中的DA和GABA神经元。先前的研究表明，不同的阿片敏感输入对阿片类药物表现出不同的敏感性，以及在慢性阿片类药物暴露后不同程度的耐受和戒断。这个项目的总体目标是描述VTA的两个不同的NAC传入细胞的特征，并发现它们如何随着急性和长期的阿片类药物暴露而变化。总的假设是，在慢性吗啡治疗后，NAC传入亚群的相对作用将发生变化。本提议的具体目的如下：(1)确定VTA中接受每个NAC投射输入的靶神经元和靶受体，(2)确定每个NAC投射到VTA的慢性吗啡诱导的适应，以及(3)确定GABAB-GIRK信号复合体对慢性吗啡的适应。总之，这些目的将阐明NAc内GABA能神经元向VTA的阿片敏感神经投射在吗啡依赖中的作用。

 DESCRIPTION (provided by applicant): Morphine is the drug of choice when treating short-term moderate to severe pain. However, prolonged use often leads to the development of tolerance and eventually dependence. The neural mechanisms of these phenotypes are not fully understood. Acutely, morphine takes action on opioid receptors in the brain resulting in inhibition of the neurons containing the receptors. In the midbrain, agonist binding to opioid receptors on GABA neurons results in disinhibition of dopamine (DA) neurons. The resulting increase in DA release is thought to contribute to the rewarding and addicting aspects of opioids. Recent evidence indicates that there are several opioid-sensitive GABA inputs to midbrain DA neurons. One such GABAergic projection originates from medium spiny neurons (MSNs) in the nucleus accumbens (NAc) and projects to the ventral tegmental area (VTA). Preliminary results indicate that both D1 and D2 DA receptor-expressing MSNs project to the VTA. These two sets of neurons express different opioid receptors (kappa and mu respectively) and synapse onto distinct target neurons. Additionally, the NAc projections target both DA and GABA neurons in the VTA. Previous research has shown that distinct opioid-sensitive inputs show different sensitivities to opioids as well as different levels of tolerance and withdrawal following chronic opioid exposure. The overall goal of this project is to characterize the two distinct NAc afferents to the VTA and discover how they change in response to acute and prolonged opioid exposure. The overall hypothesis is that the relative roles of the NAc afferent subsets will change following chronic morphine treatment. The specific aims of this proposal are as follows: (1) to identify the target neurons and target receptors in the VTA that receive input from each of the NAc projections, (2) to identify chronic morphine-induced adaptations in each of the NAc projections to the VTA, and (3) to determine the adaptations that occur in the GABAB-GIRK signaling complex in response to chronic morphine. Together, these aims will elucidate the role of the opioid-sensitive neural projection of GABAergic neurons in the NAc to the VTA in morphine dependence.