Hypocretin/Orexin Regulation of Dopamine Signaling and Cocaine Reinforcement

下丘脑分泌素/食欲素对多巴胺信号传导和可卡因强化的调节

• 批准号: 10408008
• 负责人: Rodrigo A. España
• 金额: $ 37.12万
• 依托单位: DREXEL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-01-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10408008
• 关键词: Abstinence; Acute; Animals; Arousal; Attenuated; Behavioral; Biochemistry; Brain; Chronic Disease; Cocaine; Cocaine Dependence; Cues; Development; Dopamine; Dopamine Agonists; Drug Design; Drug abuse; Drug usage; Human; Hypothalamic structure; Injections; Institutes; Lead; Mediating; Medical; Motivation; Motor Activity; Neuropeptides; Nucleus Accumbens; Peptides; Periodicity; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Phase; Post-Translational Protein Processing; Process; Psychological reinforcement; Public Health; Rattus; Recovery; Regulation; Reinforcement Schedule; Relapse; Reporting; Research; Resistance; Rewards; Scanning; Signal Transduction; System; Techniques; Testing; Ventral Tegmental Area; Work; abuse liability; addiction; antagonist; awake; base; cocaine self-administration; craving; disorder later incidence prevention; dopamine transporter; dopaminergic neuron; drug abstinence; drug craving; drug reinforcement; genetic manipulation; hypocretin; in vivo; insight; interdisciplinary approach; mesolimbic system; motivated behavior; neurochemistry; neuromechanism; neurotransmission; novel; orexin A receptor; prevent; psychostimulant; public health relevance; receptor; relapse risk; relating to nervous system; response; stimulant dependence

Project Summary: Psychostimulant addiction is a chronic disease and currently no approved pharmacotherapies exist for its treatment. Among the greatest challenges in the treatment of addiction is the prevention of relapse to drug use. In animals, periods of abstinence following drug use intensifies craving and motivation for drug, which has been associated with increased propensity for relapse. Recent advances suggest that alterations in mesolimbic dopamine systems during abstinent periods may be a critical component of the intensification of drug craving effect. Unfortunately, dopamine-based therapies are often ineffective or intolerable and may have abuse potential themselves. The hypocretins/orexins (HCRT) are hypothalamic neuropeptides that participate in the regulation of arousal, locomotor activity, and a variety of motivated behaviors. Over the past decade, the HCRT system has also been shown to influence drug reinforcement via actions in the dopamine-rich ventral tegmental area. For example, we have shown that disrupting HCRT neurotransmission within the ventral tegmental area reduces the reinforcing effects of cocaine and attenuates cocaine-induced elevations in dopamine within the nucleus accumbens. Recently we discovered a novel effect of acute HCRT disruption that causes long-lasting alterations in dopamine terminal sensitivity to cocaine and prevents increased motivation for cocaine following drug abstinence. To further examine the extent to which the HCRT system regulates dopamine signaling and cocaine reinforcement, the proposed research will employ a multidisciplinary approach using sophisticated behavioral, neurochemical, and genetic manipulation techniques. Studies will examine the utility of acute HCRT receptor 1 blockade on the development of intensified behavioral and dopaminergic responses to cocaine following a period of abstinence and whether these effects are dependent on dopamine neurons of the ventral tegmental area. Completion of this work will offer insight into the neural mechanisms underlying the addiction process and will provide the basis for a novel pharmacotherapy to treat cocaine addiction.

项目概要： 精神兴奋剂成瘾是一种慢性疾病，目前还没有批准的药物治疗其 治疗戒毒治疗方面的最大挑战之一是预防吸毒复吸。 在动物中，药物使用后的禁欲期会加剧对药物的渴望和动机， 与复发倾向的增加有关。最近的进展表明，中脑边缘系统的改变 戒断期的多巴胺系统可能是药物渴望加剧的关键组成部分 效果不幸的是，多巴胺为基础的治疗往往是无效的或无法忍受的，并可能有滥用 潜力本身。下丘脑分泌素/食欲素（HCRT）是下丘脑神经肽，参与下丘脑的神经活动。 调节唤醒、运动活动和各种动机行为。在过去的十年里，HCRT 系统也被证明通过多巴胺丰富的腹侧神经元的作用影响药物强化。 被盖区例如，我们已经证明，在腹侧破坏HCRT神经传递， 被盖区减少可卡因的强化作用，并减弱可卡因诱导的 多巴胺在脑桥核内。最近，我们发现了急性HCRT中断的新效应， 导致对可卡因的多巴胺末端敏感性的长期改变，并阻止动机的增加 在戒毒后服用可卡因为了进一步研究HCRT系统调节 多巴胺信号和可卡因强化，拟议的研究将采用多学科的方法， 运用复杂的行为神经化学和基因操控技术研究将检查 急性HCRT受体1阻滞剂对强化行为和多巴胺能神经元损伤的作用 在一段时间的禁欲后对可卡因的反应以及这些作用是否依赖于多巴胺 腹侧被盖区的神经元。这项工作的完成将提供深入了解神经机制 这是成瘾过程的基础，并将为治疗可卡因的新药物疗法提供基础。 成瘾

项目成果

Pharmacologically increasing microtubule acetylation corrects stress-exacerbated effects of organophosphates on neurons.

在药理学上增加的微管乙酰化校正了有机磷酸盐对神经元的应激效果。

• DOI: 10.1111/tra.12489
• 发表时间: 2017-07
• 期刊: Traffic (Copenhagen, Denmark)
• 作者: Rao AN;Patil A;Brodnik ZD;Qiang L;España RA;Sullivan KA;Black MM;Baas PW
• 通讯作者: Baas PW

Restoring lost nigrostriatal fibers in Parkinson's disease based on clinically-inspired design criteria.

• DOI: 10.1016/j.brainresbull.2021.07.016
• 发表时间: 2021-10
• 期刊: Brain research bulletin
• 影响因子: 3.8
• 作者: Gordián-Vélez WJ;Chouhan D;España RA;Chen HI;Burdick JA;Duda JE;Cullen DK
• 通讯作者: Cullen DK

Hypocretin / Orexin Receptor 1 Knockdown in GABA or Dopamine Neurons in the Ventral Tegmental Area Differentially Impact Mesolimbic Dopamine and Motivation for Cocaine.

腹侧被盖区 GABA 或多巴胺神经元中的下丘脑分泌素 / 食欲素受体 1 敲低对中脑边缘多巴胺和可卡因动机产生不同影响。

• DOI: 10.1016/j.addicn.2023.100104
• 发表时间: 2023
• 期刊: Addiction neuroscience
• 作者: Black,EmilyM;Samels,ShannaB;Xu,Wei;Barson,JessicaR;Bass,CarolineE;Kortagere,Sandhya;España,RodrigoA
• 通讯作者: España,RodrigoA

Selective activation of Dopamine D3 receptors and norepinephrine transporter blockade enhances sustained attention.

选择性激活多巴胺 D3 受体和去甲肾上腺素转运蛋白阻断可增强持续注意力。

• DOI: 10.1016/j.neuropharm.2019.01.003
• 发表时间: 2019
• 期刊: Neuropharmacology
• 影响因子: 4.7
• 作者: Marshall,CourtneyA;Brodnik,ZacharyD;Mortensen,OleV;Reith,MaartenEA;Shumsky,JedS;Waterhouse,BarryD;España,RodrigoA;Kortagere,Sandhya
• 通讯作者: Kortagere,Sandhya

Tissue engineered nigrostriatal pathway for treatment of Parkinson's disease.

• DOI: 10.1002/term.2698
• 发表时间: 2018-07
• 期刊: Journal of tissue engineering and regenerative medicine
• 影响因子: 3.3
• 作者: Struzyna LA;Browne KD;Brodnik ZD;Burrell JC;Harris JP;Chen HI;Wolf JA;Panzer KV;Lim J;Duda JE;España RA;Cullen DK
• 通讯作者: Cullen DK