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: 7624672
• 负责人: LYNN G KIRBY
• 金额: $ 32.12万
• 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/7624672
• 关键词: Abstinence; Acute; Affective; Agonist; Bathing; Behavioral; Behavioral Model; Brain; Cell physiology; Cells; Chronic; Clinical Treatment; Comorbidity; 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; 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; 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; depression; 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（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。即使在节制长期之后，以前的成瘾者也可能仍然容易发生复发，尤其是在压力条件下。关于阿片类药物成瘾和复发的神经生物学机制的许多研究集中在多巴胺能奖励途径的阿片类药物调节上。较少的研究研究了5-羟色胺（5-羟基丙胺; 5-HT）系统在阿片类成瘾中的作用，尤其是在单细胞水平上。 5-羟色胺系统可能有助于成瘾的情感组成部分：在戒断期间，对阿片类药物和烦躁的状态的欣快反应。长期接触阿片类药物对5-HT系统的失调也可能是情感障碍（如抑郁症具有阿片类药物依赖性）的高度合并症的基础。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励途径中发挥作用。该应用的目的是检验以下假设：血清素能背侧raphe核（DRN）受阿片类药物和压力调节，并且此神经回路是应激诱导的鸦片复发的底物。将使用电生理，免疫组织化学，药理和行为技术的组合来实现这一目标。 AIM 1将比较在体外5-HT DRN细胞中应力神经激素皮质激素释放因子（CRF）和吗啡对GABA和谷氨酸能突触活性的影响。接下来，将使用电生理学（AIM 2）和行为（AIM 3）模型研究DRN电路在应激诱导的吗啡复发中的作用。这些研究将将DRN表征为来自多个神经递质途径的输入的集成商，而阿片类药物和压力都会影响5-HT神经传递。这些研究还可以鉴定出治疗阿片类成瘾和预防复发的新目标。鸦片成瘾和复发是重要的公共卫生问题。该建议旨在研究这些条件的神经生物学基础，从单细胞生理到行为水平。这种方法可以确定治疗阿片类成瘾和预防复发的新目标。