Endocannabinoid regulation of dopamine function and reinforcement

内源性大麻素对多巴胺功能的调节和强化

基本信息

批准号：
9438372
负责人：
Daniel Patrick Covey
金额：
$ 6.3万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-02-13 至 2019-02-12
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9438372
关键词：
2-arachidonylglycerol Address Adverse effects Agonist Animals Appetitive Behavior Attenuated Automobile Driving Behavior CNR1 gene Cannabinoids Clinical Cues Data Desire for food Development Disease Dopamine Drug abuse Drug effect disorder Drug usage Elements Endocannabinoids Enzymes Future Genetic Recombination In Vitro Incentives Individual Infusion procedures Laboratories Ligands Measures Mediating MicroRNAs Modeling Monitor Motivation Mus Mutagenesis Neurons Nucleus Accumbens Obesity Optics Periodicity Pharmaceutical Preparations Pharmacology Pharmacotherapy Population Positive Reinforcements Predictive Value Presynaptic Terminals Psychological reinforcement Psychopathology Receptor Signaling Regulation Response Latencies Rewards Scanning Self Stimulation Side Specificity Techniques Testing Time Tissues United States Ventral Tegmental Area Work base cell type craving dopamine system dopaminergic neuron economic cost endocannabinoid signaling endogenous cannabinoid system health economics heuristics knock-down lipoprotein lipase neural circuit neurophysiology novel optogenetics pre-clinical presynaptic relating to nervous system therapy development

2-arachidonylglycerol Address Adverse effects Agonist Animals Appetitive Behavior Attenuated Automobile Driving Behavior CNR1 gene Cannabinoids Clinical Cues Data Desire for food Development Disease Dopamine Drug abuse Drug effect disorder Drug usage Elements Endocannabinoids Enzymes Future Genetic Recombination In Vitro Incentives Individual Infusion procedures Laboratories Ligands Measures Mediating MicroRNAs Modeling Monitor Motivation Mus Mutagenesis Neurons Nucleus Accumbens Obesity Optics Periodicity Pharmaceutical Preparations Pharmacology Pharmacotherapy Population Positive Reinforcements Predictive Value Presynaptic Terminals Psychological reinforcement Psychopathology Receptor Signaling Regulation Response Latencies Rewards Scanning Self Stimulation Side Specificity Techniques Testing Time Tissues United States Ventral Tegmental Area Work base cell type craving dopamine system dopaminergic neuron economic cost endocannabinoid signaling endogenous cannabinoid system health economics heuristics knock-down lipoprotein lipase neural circuit neurophysiology novel optogenetics pre-clinical presynaptic relating to nervous system therapy development

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项目摘要

Project Summary/Abstract Maladaptive forms of reward seeking that support drug abuse and obesity exact an enormous toll on individual and economic health. A mounting body of preclinical and clinical work demonstrates that the endocannabinoid system powerfully regulates the motivational impact of rewards. While pharmacotherapies targeting endocannabinoid function to treat disordered reward seeking are efficacious, this approach has been hindered due to non-specific drug actions and unacceptable side effects. Here, I aim to identify mechanisms by which endocannabinoids regulate reward seeking through interactions with dopamine system function to identify precise neuronal targets for future cannabinoid-based therapies. I will test the hypothesis that synthesis of the endocannabinoid 2-arachidonoylglycerol by dopamine neurons is required for dopamine neurons to encode the incentive value of reward-predicting cues and motivate reward seeking. This work will employ two cutting-edge techniques, fast-scan cyclic voltammetry and optogenetics, paired with conditional and inducible mutagenesis to selectively target the enzyme responsible for 2-arachidonoylglycerol synthesis within dopamine neurons. Our ability to target dopamine neuron function in real-time during behavior and manipulate specific elements of the endocannabinoid system will provide novel information concerning how endocannabinoid signaling motivates reward seeking, potentially enabling the development of more targeted pharmacotherapies.

项目摘要/摘要适应不良的奖励形式，寻求支持药物滥用和肥胖的确切巨大的损失和经济健康。临床前和临床工作的安装体证明了内源性大麻素系统有力地调节了奖励的动机影响。而药物疗法的靶向内源性大麻素的功能以治疗无序奖励寻求奖励有效，这种方法受到阻碍由于非特异性药物作用和不可接受的副作用。在这里，我的目的是确定机制内源性大麻素通过与多巴胺系统功能的互动来调节奖励寻求奖励以识别未来基于大麻素的疗法的精确神经元靶标。我将检验以下假设多巴胺神经元需要通过多巴胺神经元进行内源性大麻素2-芳基烯丙基甘油来编码预定奖励提示和激励寻求奖励的激励价值。这项工作将采用两个尖端技术，快速扫描的循环伏安法和光遗传学，与条件和可诱导的诱变配对有选择地靶向负责多巴胺神经元内2-芳基酮甘油合成的酶。我们的在行为过程中实时靶向多巴胺神经元功能并操纵特定元素的能力内源性大麻素系统将提供有关内源性大麻素信号如何激励的新信息寻求奖励，有潜在地开发更有针对性的药物治疗。