Neural regulation of cocaine valuation by adolescent cannabinoid exposure

 描述(申请人提供)：青少年吸食大麻是一个突出的公共卫生问题。事实上，青春期接触大麻与成年后的药物滥用和成瘾相关，并预示着未来的可卡因滥用。国家对大麻使用态度的改变以及由此推动的大麻法律改革(目前有23个州和哥伦比亚特区以某种形式使大麻合法化)突出表明，有必要审查暴露于大麻中的长期神经生物学后果。我收集的初步数据显示，青少年接触大麻类激动剂会扰乱成年后对可卡因的奖励体验，并导致可卡因诱导的条件性场所厌恶。这些数据证实了其他人的工作，表明青春期接触大麻会扰乱正常的大脑发育，并对行为产生持久的影响。在这项研究中，我们打算利用尖端的电化学和光遗传学技术来研究青春期暴露于大麻类药物对成年后可卡因体验和强化的影响。特定目的1利用药理学操作来确定青春期的大麻素暴露是否通过作用于CB1受体而对成人可卡因体验产生影响。在相同的动物中，我们将使用电化学技术快速扫描循环伏安法来测量青春期暴露于大麻是否会改变可卡因和可卡因相关背景线索诱发的亚秒多巴胺释放，并评估大麻暴露如何影响可卡因自我给药的启动和升级。特定目的2使用光遗传工具来测试大麻类物质是否通过破坏多巴胺能功能来改变可卡因体验。总之，这些实验将提供关于青春期大麻素暴露扰乱大脑发育并影响成年后可卡因奖励和强化的神经机制的新信息。

 DESCRIPTION (provided by applicant): Adolescent marijuana use is a prominent public health concern. Indeed, exposure to marijuana during adolescence is correlated with drug abuse and addiction in adulthood and predicts future cocaine abuse. Changing national attitudes on marijuana use and the resultant push for the reform of marijuana laws (23 states and the District of Columbia currently have legalized marijuana in some form) highlight a need to examine the long-term neurobiological consequences of cannabinoid exposure. I have collected preliminary data showing that adolescent exposure to a cannabinoid agonist disrupts the experience of cocaine reward in adulthood and results in cocaine-induced conditioned place aversion. These data confirm the work of others showing that cannabinoid exposure in adolescence disturbs normal brain development and produces lasting effects on behavior. In this study, we intend to utilize cutting-edge electrochemical and optogenetic techniques to investigate the effects of cannabinoid exposure in adolescence on cocaine experience and reinforcement in adulthood. Specific aim 1 utilizes pharmacological manipulations to determine if cannabinoid exposure in adolescence exerts its effects on adult cocaine experience through actions at CB1 receptors. In the same animals we will employ the electrochemical technique fast-scan cyclic voltammetry to measure whether cannabinoid exposure during adolescence changes subsecond dopamine release evoked by cocaine and cocaine-associated contextual cues and assess how cannabinoid exposure affects the initiation and escalation of cocaine self-administration. Specific aim 2 uses optogenetic tools to test whether cannabinoids alter cocaine experience through disruption of dopaminergic function. Altogether these experiments will provide novel information concerning the neural mechanisms through which cannabinoid exposure in adolescence disturbs brain development and influences cocaine reward and reinforcement in adulthood.