Investigating mechanisms mediating enhanced THC reinforcement by nicotine

项目摘要/摘要 多物质使用(PSU)非常常见，大多数药物使用治疗寻求者报告说 多种物质的使用。PSU的流行率不仅很高，而且PSU的后果也是 被认为比使用单一物质的个人更糟糕。最常见的物质之一是 与其他滥用药物一起使用的是尼古丁。大麻和尼古丁的联合使用尤其普遍， 普通人群中大麻使用的总体发生率，高达80%的大麻使用者报告说 他们也使用尼古丁。最近的流行病学研究表明，尼古丁与THC的共同使用包含 产品在增加，同时使用这两种药物的总体结果比那些 在不同的场合同时消费这两种食品的个人。因此，有必要提高我们的认识。 尼古丁和THC之间的相互作用影响的神经机制。在正在进行的研究中，我们有 开发了了解尼古丁如何影响大鼠静脉注射THC自我给药的程序。 我们发现尼古丁可显著且可逆地增加自我给药的量，并且在 同时选择程序发现，尼古丁的可获得性增强了THC自身的获得 并导致对THC的偏爱而不是尼古丁。在本提案中，我们的目标是确定 尼古丁增强四氢呋喃强化特性的机制及其同时发生的后果 尼古丁和THC自身给药对腹侧被盖区多巴胺神经元功能的影响 (VTA)。在目标1中，我们将使用VTA和伏隔核壳(NAC壳)的双色纤维光度法来 确定尼古丁对THC诱导的DA神经元活动和DA释放的影响。在目标2中，我们将使用 同时选择程序确定尼古丁增强的THC自我给药是否通过动作调节 在α7和/或包含烟碱型乙酰胆碱受体(NAChRs)的β2/4亚单位使用特定的拮抗剂。我们 将进一步确定任何一种拮抗剂是否影响尼古丁-THC介导的DA神经元活动或DA的变化 放手。最后，在目标3中，我们将使用一种新的方法来执行细胞类型特定的、基于质谱学的 蛋白质组和磷蛋白质组学分析确定尼古丁-THC自身给药对多巴胺的影响 神经元的功能仅与任何一种物质有关。DA神经元中蛋白质的邻近标记将是 这是通过依赖Cre的APEX构建体在TH-Cre大鼠中的病毒表达完成的。在结束时 在拟议的实验中，我们将确定：1)尼古丁是否增强了THC的增强作用 通过促进NAC壳中DA神经元的活性和DA的释放，2)nAChRs是 负责增强增强，以及3)共自体的蛋白质信号转导结果是什么 给予这两种物质对DA神经元功能的影响。

Project Summary/Abstract Polysubstance use (PSU) is extremely common, with the majority of substance use treatment seekers reporting the use of multiple substances. Not only is the prevalence of PSU high, but the consequences of PSU are also thought to be worse than for individuals who use single substances. One of the most common substances to be used with any other drug of abuse is nicotine. Marijuana and nicotine co-use is particularly common, with higher overall incidence of marijuana use in the general population and up to 80% of marijuana users reporting that they also use nicotine. Recent epidemiological studies indicate that the co-use of nicotine with THC containing products is increasing and those that use both drugs at the same time have worse overall outcomes than those individuals that consume both, but on separate occasions. Thus, there is a need to increase our understanding of the neural mechanisms affected by interactions between nicotine and THC. In ongoing studies, we have developed procedures for understanding how nicotine influences intravenous THC self-administration in rats. We have found that nicotine acutely and reversibly enhances the amount of THC self-administered, and in concurrent choice procedures have found that nicotine availability enhances acquisition of THC self- administration and leads to preference for THC over nicotine. In the present proposal we aim to determine the mechanisms by which nicotine enhances the reinforcing properties of THC and the consequences of concurrent nicotine and THC self-administration on the function of dopamine (DA) neurons in the ventral tegmental area (VTA). In aim 1 we will use dual-color fiber photometry in the VTA and nucleus accumbens shell (NAc shell) to determine the effects of nicotine on THC-induced DA neuron activity and DA release. In aim 2, we will use the concurrent choice procedure to determine if nicotine-enhanced THC self-administration is mediated via actions at α7 and/or β2/4 subunit containing nicotinic acetylcholine receptors (NAchRs) using specific antagonists. We will further determine if either antagonist affects nicotine-THC mediated changes in DA neuron activity or DA release. Finally, in aim 3, we will use a novel method for performing cell-type specific, mass spectrometry-based, proteomic and phosphoproteomic analysis to determine the effects of nicotine-THC self-administration on DA neuron function relative to either substance alone. Proximity labeling of proteins in DA neurons will be accomplished through Cre-dependent viral expression of the APEX construct in TH-Cre rats. At the conclusion of the proposed experiments, we will have determined: 1) if nicotine enhances the reinforcing effects of THC through promotion of increased DA neuron activity and DA release in the NAc shell, 2) which NAchRs are responsible for the enhanced reinforcement, and 3) what are the protein signaling consequences of co-self- administration of the two substances on DA neuron function.