Hypocretin/Orexin Modulation of Reward and Addiction Processes

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一个独立的系统神经科学项目。Espana博士对神经调节剂对觉醒和动机行为的作用很感兴趣。在拟议的研究计划中，Espana博士将利用自我给药、微透析和伏安技术来检查兴奋性神经肽下丘脑泌素/食欲素对奖励和成瘾过程的贡献。可卡因成瘾是一种慢性复发性疾病，其特征是尽管对身体、心理和社会产生负面影响，但仍会反复、强迫性地滥用药物。尽管在药物滥用的神经科学方面取得了巨大的进步，但现有的治疗可卡因成瘾的药物是无效的或无法忍受的，因此目前没有批准的药物疗法。下丘脑分泌素是最近发现的参与觉醒、运动活动和各种动机行为调节的神经肽。最近，新出现的证据表明，下丘脑分泌素系统对奖励功能有促进作用，这些作用涉及到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物质。为了描述下丘脑分泌素系统在觉醒和动机行为的调节中的作用，特别是与药物滥用有关的作用，本提案将研究：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伏隔核内可卡因诱导的多巴胺释放；3)下丘脑分泌素系统在多大程度上调节伏隔核内的自发多巴胺峰值活动。这项工作的完成将提供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，并将深入了解成瘾过程背后的神经机制。此外，从这些研究中获得的结果可能为产生药物滥用的新药物疗法奠定基础。

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.