Hypocretin/Orexin Modulation of Reward and Addiction Processes

下丘脑分泌素/食欲素对奖赏和成瘾过程的调节

• 批准号: 8084181
• 负责人: Rodrigo A. España
• 金额: $ 2.82万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2011-11-04
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8084181
• 关键词: Agonist; Arousal; Behavior; Chronic; Circadian Rhythms; Cocaine; Cocaine Dependence; Dopamine; Drug Addiction; Drug Design; Drug abuse; Foundations; Frequencies; Indium; Intake; K-Series Research Career Programs; Measurement; Measures; Mentors; Microdialysis; Motivation; Motor Activity; Neuromodulator; Neuropeptides; Neurosciences; Nucleus Accumbens; Pharmaceutical Preparations; Pharmacotherapy; Process; Protocols documentation; Psychological reinforcement; Recurrent disease; Regulation; Research; Rewards; SB-334867; Scanning; Self Administration; Sleep; System; Techniques; Testing; Ventral Tegmental Area; Work; addiction; base; career; dopaminergic neuron; drug abuse chemotherapy; hypocretin; insight; interdisciplinary approach; interest; motivated behavior; neuromechanism; neurotransmission; novel; programs; psychologic; receptor; reward processing; social

DESCRIPTION (provided by applicant): This Mentored Career Development Award (K01) will support Dr. Rodrigo A. Espana's long-term career objective of establishing an independent systems neuroscience program within an academic setting. Dr. Espana is interested in the actions of neuromodulators on arousal and motivated behaviors. In the proposed research program, Dr. Espana will utilize self-administration, microdialysis, and voltammetric techniques to examine the contribution of the excitatory neuropeptide hypocretin/orexin to reward and addiction processing. Cocaine addiction is a chronic relapsing disease characterized by repetitive, compulsive drug abuse despite negative physical, psychological, and social consequences. Despite huge advances in the neuroscience of drug abuse, available drugs for the treatment of cocaine addiction are ineffective or intolerable and consequently no approved pharmacotherapies currently exist. The hypocretins are relatively recently identified neuropeptides that participate in the regulation of arousal, locomotor activity, and a variety of motivated behaviors. Recently, emerging evidence indicates that the hypocretin system exerts a facilitatory influence on reward function and that these actions involve activation of dopamine neurons of the ventral tegmental area. Given the potential that the hypocretin system regulates reward associated with drug abuse, the proposed research program will employ a multidisciplinary approach to investigate hypocretin modulation of cocaine self-administration and the dopaminergic correlates that underlie these actions. To characterize the contribution of hypocretin systems in the regulation of arousal and motivated behaviors, particularly as it relates to drug abuse, this proposal will investigate: 1) The extent to which the hypocretin system influences cocaine-self administration; 2); Whether the hypocretin system participates in cocaine-induced dopamine release within the nucleus accumbens; and 3) To what degree the hypocretin systems regulates spontaneous dopamine spike activity within the nucleus accumbens. Completion of this work will provide information on the extent to which hypocretin participates in reward processing, the extent to which these actions involve the mesolimbic DA system, and will offer insight into the neural mechanisms underlying the addiction process. Further the results obtained from these studies may form the foundations to generate novel pharmacotherapies for drug abuse.

描述（由申请人提供）：这个指导的职业发展奖（K01）将支持Rodrigo A. Espana博士在学术环境中建立独立系统神经科学计划的长期职业目标。 Espana博士对神经调节剂对唤醒和动机行为的行为感兴趣。在拟议的研究计划中，ESPANA博士将利用自我管理，微透析和伏安技术来检查兴奋性神经肽降压素/Orexin对奖励和成瘾处理的贡献。可卡因成瘾是一种慢性复发疾病，其特征是重复性，强迫药物滥用，尽管身体，心理和社会后果负面。尽管药物滥用神经科学的进展很大，但可卡因成瘾治疗的可用药物是无效或无法忍受的，因此目前尚无批准的药物治疗。低载蛋白是相对较最近发现的，这些神经肽参与了唤醒，运动活性和多种动机行为的调节。最近，新兴的证据表明，降骨素系统对奖励功能产生了促进影响，并且这些作用涉及腹侧对段区域的多巴胺神经元的激活。鉴于低载素系统会调节与药物滥用相关的奖励的潜力，因此拟议的研究计划将采用多学科方法来研究可卡因自我给药的低载素调节，并且多巴胺能与这些行为相关。为了表征下胚素系统在唤醒和动机行为的调节中的贡献，尤其是在与药物滥用有关的情况下，该提案将研究：1）降骨素系统影响可卡因自由的给药的程度； 2）;低载素系统是否参与可卡因诱导的伏隔核中的多巴胺释放。 3）降压素系统在多大程度上调节伏隔核中自发的多巴胺峰活动。这项工作的完成将提供有关降囊蛋白参与奖励处理的程度的信息，这些行动在多大程度上涉及中唇型DA系统，并将深入了解成瘾过程中的神经机制。此外，从这些研究中获得的结果可能构成基础，以产生用于药物滥用的新药物疗法。