Role of Serotonin 5-HT2C Receptor Signaling in Cocaine Cue Reactivity

血清素 5-HT2C 受体信号在可卡因提示反应中的作用

• 批准号: 8527378
• 负责人: Sarah E. Swinford-Jackson
• 金额: $ 2.98万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-05-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8527378
• 关键词: Abbreviations; Abstinence; Agonist; Association Learning; Behavior; Behavioral; Biochemical; Biological Assay; Biology; Brain; Brain Diseases; Chronic; Co-Immunoprecipitations; Cocaine; Cocaine Abuse; Cocaine Dependence; Cognitive; Complex; Coupling; Cues; Data; Dependovirus; Dimensions; Dopamine; Dose; Drug Delivery Systems; Event; Exhibits; Experimental Designs; Face; GTP-Binding Proteins; Genes; Goals; Guanosine Triphosphate; Homeostasis; Human; Immunohistochemistry; Knowledge; Link; Literature; MAPK3 gene; Maintenance; Mediating; Methodology; Microinjections; Mitogen-Activated Protein Kinases; Modeling; Molecular; Neurobiology; Neurons; Neuropharmacology; Nucleus Accumbens; Output; Pathway interactions; Pharmaceutical Preparations; Pharmacotherapy; Phenotype; Prefrontal Cortex; Process; Psychostimulant dependence; Public Health; Rattus; Receptor Mediated Signal Transduction; Receptor Signaling; Regulation; Relapse; Relative (related person); Role; Safety; Self Administration; Serotonin; Serotonin Receptor 5-HT2C; Signal Transduction; Stimulus; System; Testing; Therapeutic; Training; Treatment outcome; United States; Ventral Tegmental Area; base; behavioral pharmacology; cost; cue reactivity; dependence relapse; disorder later incidence prevention; drug discovery; drug seeking behavior; gamma-Aminobutyric Acid; improved; innovation; neurochemistry; neurotransmission; novel; pre-clinical; protein expression; public health relevance; receptor; receptor expression; receptor function; reinforcer; relating to nervous system; research study; response; small hairpin RNA; translational study; treatment strategy

DESCRIPTION (provided by applicant): Cocaine abuse and vulnerability to dependence and relapse during abstinence is one of the great challenges on the public health agenda of the United States, with an enormous cost in human tragedy as well as in public health and safety. An improved understanding of the mechanisms underlying cocaine dependence and relapse is necessary to generate new pharmacological and behavioral strategies for treatment. Vulnerability to environmental cues previously associated with cocaine-taking behavior ("cue reactivity") is thought to promote cycles of dependence and relapse, a neural process that involves the mesocorticoaccumbens dopamine (DA) pathway which arises in the ventral tegmental area (VTA). A considerable literature has implicated the VTA in the brain and behavioral response to cocaine-associated cues, although our knowledge of the neurochemical afferents to the VTA that control cue reactivity is limited. Serotonin (5-HT) terminals densely innervate VTA neurons which express the 5-HT2C receptor (5-HT2CR); activation of the 5-HT2CR exerts an overall inhibitory influence over the function of the VTA and related cocaine-mediated behaviors. Thus, the 5-HT2CR in the VTA provides functional tone over behavior; however, the role for VTA 5-HT2CR signaling in cue reactivity has yet to be explored. Our long term goal is to elucidate the contribution of 5-HT2CR regulation to cue reactivity as a means to identify novel pharmacological approaches for treating cocaine addiction. The objective of this proposal is to employ innovative and complementary behavioral, biochemical and pharmacological approaches to identify differences in the status of 5-HT2CR function that contribute to expression of the high vs. low cue reactivity phenotype and to manipulate this system to test specific hypotheses regarding a role for the 5-HT2CR in cocaine-seeking behavior. The following aims will test our the overarching hypothesis that malfunctional 5- HT2CR signal transduction in the VTA emerges during forced abstinence from cocaine self-administration to drive the high cue reactivity phenotype: (1) interrogate VTA 5-HT2CR localization and signal transduction in cue reactivity phenotypes; (2) identify functional sensitivity of VTA 5-HT2CR signal transduction in cue reactivity phenotypes; (3) assess the impact of VTA 5-HT2CR knockdown on cue reactivity.. Upon completion, the applicant will acquire training and knowledge in new concepts and methodologies including the neurobiology of cue reactivity and psychostimulant addiction, the experimental design and analyses of behavioral pharmacology, neurochemical, and virally-mediated gene manipulations, and translational neuropharmacology principles. These innovative, translational studies will be the first to systematically explore the functional contribution of VTA 5-HT2CR in cue reactivity following an extended period of abstinence. The neurobiological understanding of how 5-HT2CR homeostasis within the mesocorticoaccumbens circuit contributes to the dynamic events underlying persistent maladaptive behaviors associated with cocaine dependence will allow for the exploration of new molecular entities to suppress cue reactivity and minimize relapse in cocaine addiction.

描述（由申请人提供）：可卡因滥用和戒酒期间依赖和复发的脆弱性是美国公共卫生议程的巨大挑战之一，在人类的悲剧以及公共卫生和安全方面付出了巨大的代价。对可卡因依赖性和复发的机制的改进理解对于产生新的药理和行为策略是必要的。人们认为，与可卡因摄取行为相关的环境提示（“提示反应性”）被认为可以促进依赖性和复发的周期，这是一种涉及腹侧偏段区域（VTA）中产生的中皮层辅助疗法多巴胺（DA）途径的神经过程。尽管我们对控制提示反应性的VTA的神经化学传入的了解受到限制，但大量文献牵涉到大脑中的VTA和对可卡因相关的提示的行为反应。羟色胺（5-HT）末端密度支配VTA神经元，表达5-HT2C受体（5-HT2CR）； 5-HT2CR的激活对VTA和相关可卡因介导的行为的功能产生了总体抑制作用。因此，VTA中的5-HT2CR提供了对行为的功能语调。但是，VTA 5-HT2CR信号在提示反应性中的作用尚未探索。我们的长期目标是阐明5-HT2CR调节对提示反应性的贡献，作为确定可卡因成瘾的新型药理方法的一种手段。该提案的目的是采用创新和互补的行为，生化和药理学方法来确定5-HT2CR功能状态的差异，这有助于表达高线索和低提示反应性表型，并操纵该系统以测试5-HT2CR在可cocaine-eyek-etheek-etheek-etheeking-etheek-etheek-etheek-etheek-geeking cartion中的特定假设。以下目的将检验我们的总体假设，即VTA中发生的5- HT2CR信号转导，在从可卡因自我给药中强迫禁欲时出现了以驱动高提示反应性表型的强迫禁欲：（1）询问VTA 5-HT2CR定位和提示反应性表型中的VTA 5-HT2CR定位和信号转导； （2）确定提示反应性表型中VTA 5-HT2CR信号转导的功能灵敏度； （3）评估VTA 5-HT2CR敲低对提示反应性的影响。.完成后，申请人将在新概念和方法中获取培训和知识，包括提示反应性和心理刺激性成瘾的神经生物学，实验性设计和行为药理学，神经化学药理，神经化学作用，神经化学和病毒介导的基因学原理和翻译性的Neurofors和Translational Neurofars和Translational Neurofranc。这些创新的转化研究将是第一个系统地探索VTA 5-HT2CR在延长禁欲后提示反应性的功能贡献的研究。神经生物学对中皮层辅助电路中的5-HT2CR稳态如何有助于与可卡因依赖性相关的持续性疾病疾病行为的动态事件，从而使新分子实体探索新分子实体可以抑制提示反应性并最大程度地减少可卡因的复发性。