Hypocretin/Orexin Modulation of Reward and Addiction Processes

描述(由申请者提供)：这一指导职业发展奖(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。埃斯帕纳博士感兴趣的是神经调节剂对唤醒和动机行为的作用。在拟议的研究计划中，埃斯帕纳博士将利用自我给药、微透析和伏安技术来研究兴奋性神经肽下丘脑/食欲素在奖赏和成瘾过程中的作用。可卡因成瘾是一种慢性复发性疾病，其特征是反复、强迫滥用药物，尽管存在负面的生理、心理和社会后果。尽管药物滥用的神经科学取得了巨大进展，但现有的治疗可卡因成瘾的药物无效或无法耐受，因此目前还不存在经批准的药物疗法。下丘脑分泌素是最近发现的神经肽，参与觉醒、运动活动和各种动机行为的调节。最近，新的证据表明，下丘脑系统对奖赏功能有易化作用，这些作用涉及腹侧被盖区的多巴胺神经元的激活。考虑到下丘脑泌素系统调节与药物滥用相关的奖赏的可能性，拟议的研究计划将采用多学科方法来研究下丘脑泌素对可卡因自我管理的调节以及这些作用背后的多巴胺能关联。为了确定下丘脑系统在调节觉醒和动机行为中的作用，特别是在与药物滥用有关的过程中，本研究将调查：1)下丘脑系统对可卡因自身给药的影响程度；2)下丘脑系统是否参与可卡因诱导的伏核内多巴胺的释放；3)下丘脑系统在多大程度上调节伏隔核内自发的多巴胺峰活动。这项工作的完成将提供有关下丘脑肌素参与奖赏处理的程度、这些活动涉及中脑边缘DA系统的程度的信息，并将提供对成瘾过程潜在神经机制的洞察。此外，从这些研究中获得的结果可能成为产生针对药物滥用的新的药物疗法的基础。

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.