Regulation of Serotonin Circuits in Opiate Addiction and Relapse

描述（由申请人提供）：阿片类药物在疼痛的临床治疗中非常有效，但持续给药会导致耐受性的发展，并可能导致成瘾。即使在长期戒断之后，前成瘾者仍然容易复发，特别是在压力条件下。阿片类药物成瘾和复吸的神经生物学机制的研究主要集中在阿片类药物对多巴胺能奖赏通路的调节。很少有研究探讨5-羟色胺（5-HT）系统在阿片成瘾中的作用，特别是在单细胞水平。5-羟色胺系统可能有助于成瘾的情感成分：对阿片类药物的欣快反应和戒断期间的焦虑状态。长期暴露于阿片类药物引起的5-HT系统失调也可能是情感障碍如抑郁症与阿片类药物依赖的高共病率的基础。此外，5-HT系统调节多巴胺能神经传递，因此可能间接地在更传统的奖赏途径中发挥作用。本申请的目的是测试的假设，即多巴胺能中缝背核（DRN）调节阿片类药物和压力，此外，这个神经回路是应激诱导的阿片类药物复发的基板。这一目标将通过电生理学、免疫组织化学、药理学和行为学技术的组合来实现。目的1比较应激神经激素促肾上腺皮质激素释放因子（CRF）和吗啡对体外培养的5-HT DRN细胞GABA能和多巴胺能突触活动的影响。接下来，将使用电生理（AIM 2）和行为（AIM 3）模型研究DRN回路在应激诱导的吗啡复吸中的作用。这些研究将把DRN描述为来自多种神经递质通路的输入的集成器，这些神经递质通路被阿片类药物和压力参与，以影响5-HT神经传递。这些研究还可能确定治疗阿片类药物成瘾和预防复发的新靶点。阿片成瘾和复吸是重大的公共卫生问题。该提案旨在从单细胞生理学到行为水平研究这些条件的神经生物学基础。这种方法可以确定新的目标，阿片类药物成瘾的治疗和预防复发。

DESCRIPTION (provided by applicant): Opioids are highly effective in the clinical treatment of pain but sustained administration results in the development of tolerance and may lead to addiction. Even after prolonged abstinence, former addicts can remain vulnerable to relapse, particularly under stressful conditions. Much research on the neurobiological mechanisms of opiate addiction and relapse has focused on opioid regulation of dopaminergic reward pathways. Fewer studies have examined the role of the serotonin (5-hydroxytryptamine; 5-HT) system in opiate addiction, particularly at the single cell level. The serotonin system may contribute to the affective components of addiction: both euphoric responses to opiates and dysphoric states during withdrawal. Dysregulation of the 5-HT system by long-term exposure to opiates may also underlie the high rate of comorbidity of affective disorders such as depression with opiate dependence. In addition, the 5-HT system regulates dopaminergic neurotransmission, thus may indirectly play a role in more traditional reward pathways. The objective of this application is to test the hypothesis that the serotonergic dorsal raphe nucleus (DRN) is regulated by opioids and stress and furthermore that this neural circuit is a substrate for stress-induced opiate relapse. This objective will be achieved using a combination of electrophysiological, immunohistochemical, pharmacological and behavioral techniques. AIM 1 will compare the effects of the stress neurohormone corticotropin-releasing factor (CRF) and morphine on GABA- and glutamatergic synaptic activity in 5-HT DRN cells in vitro. Next, the role of DRN circuits in stress-induced morphine relapse will be investigated using electrophysiological (AIM 2) and behavioral (AIM 3) models. These studies will characterize the DRN as an integrator of inputs from multiple neurotransmitter pathways that are engaged by both opioids and stress to impact 5-HT neurotransmission. These studies may also identify novel targets for the treatment of opiate addiction and the prevention of relapse. Opiate addiction and relapse are significant public health concerns. This proposal aims to investigate the neurobiological basis for these conditions from single cell physiology to behavioral levels. This approach may identify novel targets for the treatment of opiate addiction and the prevention of relapse.