Endocannabinoid regulation of dopamine function and reinforcement

项目总结/摘要 支持药物滥用和肥胖的不适应性形式的奖励寻求对个体造成了巨大的损失 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 系统有力地调节了奖励的激励作用。虽然药物治疗针对 内源性大麻素的功能，以治疗紊乱的奖励寻求是有效的，这种方法已受到阻碍 由于非特异性药物作用和不可接受的副作用。在这里，我的目标是确定机制， 内源性大麻素通过与多巴胺系统功能的相互作用来调节奖赏寻求， 未来大麻素类药物治疗的精确神经靶点。我将测试的假设，合成的 多巴胺神经元需要内源性大麻素2-花生四烯酸甘油来编码 奖励预测线索的激励价值和激励奖励寻求。这项工作将聘请两个尖端 技术，快速扫描循环伏安法和光遗传学，与条件和诱导诱变配对， 选择性靶向多巴胺神经元内负责2-花生四烯酸甘油合成的酶。我们 能够在行为过程中实时靶向多巴胺神经元功能， 内源性大麻素系统将提供有关内源性大麻素信号如何激发 奖励寻求，可能使更有针对性的药物治疗的发展。

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.