Regulation of Serotonin Circuits in Opiate Addiction and Relapse

阿片成瘾和复发中血清素回路的调节

• 批准号: 7294920
• 负责人: LYNN G KIRBY
• 金额: $ 32.77万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-30 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7294920
• 关键词: Abstinence; Acute; Affective; Agonist; Bathing; Behavioral; Behavioral Model; Brain; Cell physiology; Cells; Chronic; Clinical Treatment; Comorbidity; Condition; Corticotropin-Releasing Hormone; Corticotropin-Releasing Hormone Receptors; Data; Development; Excitatory Amino Acid Antagonists; Exposure to; GABA Agonists; GABA Antagonists; Glutamate Agonist; Glutamates; Immunohistochemistry; In Vitro; Laboratories; Lead; Mediating; Mental Depression; Modeling; Mood Disorders; Morphine; Morphine Dependence; Narcotic Antagonists; Neurobiology; Neurohormones; Neurons; Neurotransmitters; Opiate Addiction; Opiates; Opioid; Opioid Receptor; Pain; Pathway interactions; Pharmaceutical Preparations; Play; Public Health; Rate; Recording of previous events; Regulation; Relapse; Research; Research Personnel; Rewards; Role; Serotonin; Serotonin Receptor 5-HT1A; Serotonin Uptake Inhibitors; Site; Slice; Stress; Synapses; System; Techniques; Testing; Whole-Cell Recordings; Withdrawal; acute stress; addiction; base; disorder later incidence prevention; dorsal raphe nucleus; gamma-Aminobutyric Acid; inhibitor/antagonist; neural circuit; neurobiological mechanism; neuronal cell body; neurotransmission; novel; opioid abuse; postsynaptic; preference; presynaptic; programs; receptor; response; serotonergic regulation

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.

描述(申请人提供)：阿片类药物在临床治疗疼痛方面非常有效，但持续给药会导致耐受性的发展，并可能导致成瘾。即使在长期戒除之后，曾经的吸毒者仍然很容易复发，特别是在压力很大的情况下。关于阿片成瘾和复发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。很少有研究研究5-羟色胺(5-羟色胺；5-羟色胺)系统在阿片成瘾中的作用，特别是在单细胞水平上。5-羟色胺系统可能有助于成瘾的情感成分：对鸦片类药物的愉悦反应和戒断过程中的烦躁状态。长期接触阿片类药物导致的5-羟色胺系统调节失调也可能是导致抑郁症与阿片类药物依赖等情感障碍高共病的原因。此外，5-羟色胺系统调节多巴胺能神经传递，因此可能在更传统的奖赏通路中间接发挥作用。这一应用的目的是验证5-羟色胺能中缝背核(DRN)受阿片类药物和应激调节的假说，以及该神经回路是应激诱导的阿片类药物复发的底物的假说。这一目标将使用电生理、免疫组织化学、药理学和行为技术的组合来实现。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-HTDRN细胞GABA能和谷氨酸能突触活动的影响。接下来，将使用电生理(AIM 2)和行为(AIM 3)模型来研究DRN回路在应激诱导的吗啡复发中的作用。这些研究将把DRN描述为多个神经递质通路的输入的整合者，阿片类药物和应激都参与了这些通路，从而影响5-羟色胺的神经传递。这些研究还可能确定治疗阿片成瘾和预防复发的新靶点。鸦片成瘾和复发是严重的公共卫生问题。这项建议旨在从单细胞生理学到行为水平研究这些疾病的神经生物学基础。这种方法可以确定治疗阿片成瘾和预防复发的新靶点。