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）：该导师职业发展奖 (K01) 将支持 Rodrigo A. Espana 博士的长期职业目标，即在学术环境中建立独立的系统神经科学项目。 Espana 博士对神经调节剂对唤醒和动机行为的作用感兴趣。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下丘脑分泌素/食欲素对奖励和成瘾处理的贡献。可卡因成瘾是一种慢性复发性疾病，其特点是反复、强迫性滥用药物，尽管会造成身体、心理和社会方面的负面后果。尽管药物滥用的神经科学取得了巨大进步，但用于治疗可卡因成瘾的现有药物无效或无法耐受，因此目前尚不存在经批准的药物疗法。下丘脑分泌素是最近才发现的神经肽，参与调节觉醒、运动活动和各种动机行为。最近，新出现的证据表明下丘脑分泌素系统对奖赏功能发挥促进作用，并且这些作用涉及腹侧被盖区多巴胺神经元的激活。鉴于下丘脑分泌素系统调节与药物滥用相关的奖励的潜力，拟议的研究计划将采用多学科方法来研究下丘脑分泌素对可卡因自我给药的调节以及这些行为背后的多巴胺能相关性。为了描述下丘脑分泌素系统在调节唤醒和动机行为方面的贡献，特别是与药物滥用相关的作用，本提案将调查： 1) 下丘脑分泌素系统影响可卡因自我给药的程度； 2);下丘脑分泌素系统是否参与可卡因诱导的伏核内多巴胺释放； 3）下丘脑分泌素系统在多大程度上调节伏隔核内自发的多巴胺尖峰活动。这项工作的完成将提供有关下丘脑分泌素参与奖励处理的程度、这些行为涉及中脑边缘 DA 系统的程度的信息，并将提供对成瘾过程背后的神经机制的深入了解。此外，从这些研究中获得的结果可能为开发针对药物滥用的新药物疗法奠定基础。