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

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要：精神刺激成瘾是一种慢性疾病，目前尚无批准的药物治疗治疗。成瘾治疗的最大挑战之一是预防吸毒复发。在动物中，药物使用后的禁欲时期加剧了对药物的渴望和动力，这有与复发倾向的增加有关。最近的进步表明，中左右的变化戒酒时期的多巴胺系统可能是药物渴望加强的关键组成部分影响。不幸的是，基于多巴胺的疗法通常是无效或无法忍受的，可能会滥用潜力。低载染素/甲氧素（HCRT）是参与参与的下丘脑神经肽调节唤醒，运动活动和各种动机行为。在过去的十年中，HCRT 还显示系统通过富多巴胺的腹侧的作用影响药物加强支段区域。例如，我们已经表明，腹侧的HCRT神经传递破坏换段区域降低了可卡因的增强作用，并减轻了可卡因诱导的海拔伏隔核中的多巴胺。最近，我们发现了急性HCRT破坏的新型效果导致多巴胺末端对可卡因的敏感性的长期变化，并防止动机增加用于戒毒后可卡因。进一步检查HCRT系统调节的程度多巴胺信号传导和可卡因增强，拟议的研究将采用多学科方法使用复杂的行为，神经化学和遗传操纵技术。研究将检查急性HCRT受体1封锁的效用，对不断增强的行为和多巴胺能的发展戒酒期之后对可卡因的反应以及这些作用是否取决于多巴胺腹侧盖区域的神经元。这项工作的完成将洞悉神经机制基本成瘾过程，将为可卡因治疗可卡因的新型药物疗法提供基础瘾。

项目成果

期刊论文数量（26）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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

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

DOI：
10.1111/tra.12489
发表时间：
2017-07
期刊：
Traffic (Copenhagen, Denmark)
影响因子：
0
作者：
Rao AN;Patil A;Brodnik ZD;Qiang L;España RA;Sullivan KA;Black MM;Baas PW
通讯作者：
Baas PW

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
影响因子：
0
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

Hypocretin receptor 1 blockade preferentially reduces high effort responding for cocaine without promoting sleep.