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.

项目总结/摘要 多物质使用（PSU）是非常普遍的，大多数物质使用治疗寻求者报告 使用多种物质。不仅PSU的患病率很高，而且PSU的后果也很严重。 被认为比使用单一物质的人更糟糕。最常见的物质之一， 与其他药物一起使用的是尼古丁。大麻和尼古丁的共同使用是特别常见的， 一般人群中大麻使用的总体发生率和高达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，尼古丁与含THC的药物合用， 同时使用这两种药物的人的总体结果比那些同时使用这两种药物的人更差。 两种食物都有，但在不同的场合。因此，有必要增进我们的了解， 尼古丁和四氢大麻酚相互作用的神经机制。在正在进行的研究中，我们 研究人员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。 我们已经发现，尼古丁急性和可逆地增加THC自我管理的量， 同时选择程序发现，尼古丁的可用性增强了THC自身的获得， 给药并导致THC优于尼古丁。在本提案中，我们的目标是确定 尼古丁增强THC的强化特性的机制以及同时 尼古丁和四氢大麻酚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，我们将在VTA和Nac壳层（NAc壳层）中使用双色光纤光度法， 确定尼古丁对THC诱导的DA神经元活性和DA释放的影响。在目标2中，我们将使用 同时选择程序，以确定尼古丁增强的THC自我给药是否通过作用介导 在α7和/或β2/4亚基含有烟碱乙酰胆碱受体（NAchR）使用特定的拮抗剂。我们 将进一步确定任一拮抗剂是否影响烟碱-THC介导的DA神经元活性或DA release.最后，在目标3中，我们将使用一种新的方法进行细胞类型特异性，基于质谱， 蛋白质组学和磷酸蛋白质组学分析以确定尼古丁-THC自身给药对DA的影响 神经元功能相对于单独的物质。DA神经元中蛋白质的邻近标记将是 通过TH-Cre大鼠中APEX构建体的Cre依赖性病毒表达来实现。结束时 在所提出的实验中，我们将确定：1）尼古丁是否增强了THC的强化作用 通过促进增加的DA神经元活性和NAc壳中的DA释放，2）哪些NAchR是 负责增强强化，和3）什么是蛋白质信号传导的后果，共同自我- 这两种物质的给药对DA神经元功能的影响。