Endocannabinoid regulation of dopamine function and reinforcement

项目摘要/摘要 支持药物滥用和肥胖的不适应形式的奖励寻求给个人造成了巨大的损失 和经济健康。越来越多的临床前和临床工作表明，内源性大麻素 制度有力地规范了奖励的激励影响。在药物治疗靶向的同时 内源性大麻素功能对治疗寻求奖赏障碍是有效的，这一途径受到了阻碍 由于非特定的药物作用和不可接受的副作用。在这里，我的目标是确定通过哪些机制 内源性大麻素通过与多巴胺系统功能相互作用调节奖赏寻求 未来大麻类药物治疗的精确神经元靶点。我将测试这一假设，即合成的 多巴胺神经元需要内源性大麻素2-花生酰甘油来编码 奖励的激励价值--预测线索和激励奖励寻求。这项工作将使用两个尖端的 快速扫描循环伏安和光遗传学技术，结合条件诱变和诱变 选择性地靶向多巴胺神经元内负责合成2-花生四烯基甘油的酶。我们的 能够在行为过程中实时定位多巴胺神经元的功能，并操纵 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，潜在地使更有针对性的药物疗法的开发成为可能。

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.