Regulation of Serotonin Circuits in Opiate Addiction and Relapse

描述（由申请人提供）：阿片类药物在临床治疗疼痛方面非常有效，但持续服用会导致耐受性的发展，并可能导致成瘾。即使经过长时间的戒断，以前的成瘾者仍然容易复发，特别是在有压力的情况下。许多关于阿片成瘾和复发的神经生物学机制的研究都集中在阿片调节多巴胺能奖励通路上。很少有研究检查5-羟色胺（5-羟色胺；5-HT）系统在阿片类药物成瘾中的作用，特别是在单细胞水平上。血清素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不安状态。长期接触阿片类药物导致的5-羟色胺系统失调也可能是阿片类药物依赖导致抑郁症等情感性疾病高发的原因。此外，5-HT系统调节多巴胺能神经传递，因此可能在更传统的奖励途径中间接发挥作用。本研究的目的是验证5 -羟色胺能中隔背核（DRN）受阿片类药物和应激调节的假设，以及该神经回路是应激诱导阿片类药物复发的基础。这一目标将通过结合电生理、免疫组织化学、药理学和行为学技术来实现。AIM 1将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5-HT DRN细胞GABA-和谷氨酸能突触活性的影响。接下来，我们将利用电生理（AIM 2）和行为（AIM 3）模型研究DRN回路在应激诱导吗啡复发中的作用。这些研究将DRN描述为阿片类药物和应激影响5-羟色胺神经传递的多种神经递质通路输入的整合者。这些研究还可能确定治疗阿片成瘾和预防复发的新靶点。阿片类药物成瘾和复发是重大的公共卫生问题。本提案旨在从单细胞生理学到行为水平研究这些情况的神经生物学基础。这种方法可以确定治疗阿片成瘾和预防复发的新靶点。

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.