Investigating mechanisms mediating enhanced THC reinforcement by nicotine

研究尼古丁增强 THC 增强作用的机制

• 批准号: 10739859
• 负责人: Mary M Torregrossa
• 金额: $ 53.57万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10739859
• 关键词: Acute; Address; Adoption; Affect; Alcohols; Animal Model; Animals; Area; Biotinylation; Brain; Cannabis; Catheters; Choices and Control; Clinical; Cognitive; Color; Consumption; Control Groups; Dopamine; Drug Combinations; Drug Exposure; Drug Interactions; Drug user; Fiber; General Population; Glutamates; Implant; Incidence; Individual; Intake; Intravenous; Intravenous infusion procedures; Investigation; Knowledge; Label; Left; Marijuana; Mass Spectrum Analysis; Measures; Mediating; Methods; Modeling; Motivation; National Institute of Drug Abuse; Neuronal Plasticity; Neurons; Nicotine; Nicotinic Receptors; Nucleus Accumbens; Outcome; Pharmaceutical Preparations; Phosphorylation; Photometry; Prevalence; Procedures; Property; Proteins; Proteomics; Psychological reinforcement; Public Health; Rattus; Relapse; Reporting; Research; Rewards; Role; Saline; Self Administration; Signal Transduction; Signaling Protein; Speed; Structure of jugular vein; System; Testing; Tetrahydrocannabinol; Time; Tyrosine 3-Monooxygenase; Ventral Tegmental Area; Viral; addiction; antagonist; cannabinoid receptor; cell type; comparison group; design; dopaminergic neuron; drug of abuse; epidemiologic data; epidemiology study; experimental study; functional outcomes; gamma-Aminobutyric Acid; insight; marijuana use; marijuana user; neural; neurobiological mechanism; neuromechanism; nicotine use; novel; phosphoproteomics; polysubstance use; pre-clinical; pre-clinical research; preference; receptor; response; social; substance use; substance use treatment; tobacco smokers; transmission process

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.

项目摘要/摘要 多数使用（PSU）非常普遍，大多数药物使用治疗者报告了 使用多种物质。不仅PSU的流行率很高，而且PSU的后果也是 被认为比使用单一物质的人还要糟糕。最常见的物质之一 与任何其他滥用药物一起使用的是尼古丁。大麻和尼古丁共用尤其常见，更高 大麻在普通人群中使用的总体事件，多达80％的大麻用户报告 他们还使用尼古丁。最近的流行病学研究表明，尼古丁与含THC的共同使用 产品正在增加，同时使用两种药物的产品的总体结果比 同时消费但在不同场合消费的个人。那是有必要提高我们的理解 受尼古丁与THC之间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内THC自我给药的程序。 我们发现尼古丁敏锐而可逆地增强了THC自我管理的数量，并在 并发选择程序发现尼古丁的可用性增强了THC自我的获取 给药并导致偏爱THC而不是尼古丁。在本提案中，我们旨在确定 尼古丁增强了THC的增强特性的机制和并发的后果 关于多巴胺（DA）神经元在腹侧段区域的功能的尼古丁和THC自我给药 （VTA）。在AIM 1中，我们将在VTA中使用双色纤维光度法和伏隔核（NAC壳）到 确定尼古丁对THC诱导的DA神经元活性和DA释放的影响。在AIM 2中，我们将使用 并发选择程序以确定尼古丁增强的THC自我管理是否是通过动作介导的 使用特定拮抗剂，在含有烟碱乙酰胆碱受体（NACHRS）的α7和/或β2/4亚基处。我们 将进一步确定拮抗剂是否影响尼古丁-THC介导的DA神经元或DA的变化 发布。最后，在AIM 3中，我们将使用一种新方法来执行细胞类型的特异性，基于质谱的特异性方法， 蛋白质组学和磷酸化蛋白质组学分析，以确定尼古丁-THC自我给药对DA的影响 神经元功能相对于单独的任何一种物质。 DA神经元中蛋白质的接近标记将是 通过依赖CRE的病毒表达在Th-cre大鼠中的CRE依赖性病毒表达完成。结论 在提出的实验中，我们将确定：1）如果尼古丁增强了THC的增强作用 通过促进NAC壳中增加的DA神经元活性和DA释放，2）NACHR是 负责增强的加固，以及3）蛋白质信号传导的后果是什么 在DA神经元功能上给予两种物质。