Cannabinoid receptor control of a DRN to VTA pathway and its role in affective states

大麻素受体对 DRN 至 VTA 通路的控制及其在情感状态中的作用

• 批准号: 10316215
• 负责人: Joseph F Cheer
• 金额: $ 34.76万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10316215
• 关键词: Ablation; Acute; Adolescence; Adolescent; Adult; Adverse event; Affective; Anatomy; Area; Axon; Behavior; Brain; CNR1 gene; Cannabinoids; Chronic; Clinical; Consumption; Coupled; Cre lox recombination system; Crisis Intervention; Cues; Data; Development; Disease; Dopamine; Electrophysiology (science); Endocannabinoids; Enterobacteria phage P1 Cre recombinase; Exposure to; Female; Functional disorder; Funding; Future; GTP-Binding Proteins; Gene Transfer; Genetic; Harm Reduction; High School Student; Human; Impairment; Incidence; Investigation; Laboratories; Laboratory Finding; Life; Ligands; Light; Link; Literature; Marijuana; Mediating; Mental Depression; Messenger RNA; Mission; Monitor; Mood Disorders; Moods; Motivation; National Institute of Drug Abuse; Neuromodulator; Neurons; Nucleus Accumbens; Opsin; Optics; Pathologic; Pathway interactions; Pattern; Periodicity; Phase; Population; Populations at Risk; Probability; Property; Public Opinion; Receptor Activation; Receptor Signaling; Recovery; Regulation; Reporting; Research; Rewards; Role; Scanning; Serotonergic System; Serotonin; Shapes; Signal Transduction; Stress; Syndrome; System; THC exposure; Testing; Tetrahydrocannabinol; Therapeutic; Time; Ventral Tegmental Area; Viral; Work; addiction; cannabinoid receptor; cell type; dopaminergic neuron; dorsal raphe nucleus; dynamic system; endogenous cannabinoid system; exogenous cannabinoid; experience; experimental study; gain of function; insight; loss of function; male; marijuana use; mature animal; monoamine; motivated behavior; mouse model; negative affect; neurobiological mechanism; neurotransmitter release; optogenetics; pre-clinical; preservation; receptor; receptor expression; response; tool; treatment strategy; twelfth grade; vector

PROJECT SUMMARY Dopaminergic and serotonergic systems of the brain are associated with many psychiatric conditions including addiction and depression. However, there has been less investigation regarding how these systems dynamically interact to modulate changes in motivation following adverse events in early life and how they regulate responses leading to recovery and gain of function. For example, clinical and preclinical findings that exposure to exogenous cannabinoids such as Δ9-tetrahydrocannabinol (THC, the main psychoactive component of marijuana) during adolescence, leads to motivational deficits similar to those caused by stress that are consistent with compromised affective states such as depression. Exciting preliminary work from our laboratory shows that serotonin (5HT) release in the ventral tegmental area (VTA) excites dopamine (DA) neurons, enhances phasic DA release in the nucleus accumbens (NAc) and is reinforcing. Our preliminary data also suggests that potential counter-motivational effects of adolescent THC can arise from a decrease in the probability of neurotransmitter release from 5HT terminals in the VTA caused by activation of CB1 receptors on these axons. Here, we propose two experiments to investigate the functional role of CB1 receptors on 5HT terminals in the VTA. First, we will control CB1 receptor expression via cre-lox recombination approaches involving cell-type specific loss of function and rescue to isolate the role of CB1 receptors on VTA 5HT terminals to probe cue-related dopaminergic encoding of motivated behavior (aim 1). Next, we will determine if chronic adolescent exposure to THC reduces motivation and its dopaminergic correlates in adulthood and whether these maladaptive effects require CB1 receptors expressed on 5HT terminals in the VTA (aim 2). The present study will incorporate a combination of behavior, anatomy, electrophysiology, fast-scan cyclic voltammetry, virally-mediated gene transfer and optogenetics. In addition, experiments will include males and females and will be replicated in adult animals. Specific genetic control of CB1 receptors on 5HT afferents to VTA DA neurons and optogenetic interrogation of this circuit, will allow explicit tests of current hypotheses of endocannabinoid function in motivation and the consequences of its dysfunction following THC exposure in adolescence. Thus, by investigating 5HT terminal/DA interactions with CB1 receptor signaling, the present proposal makes use of tools not yet applied to these questions to respond to NIDA's mission and to generate new insights on therapeutic strategies for the treatment of conditions involving compromised motivation.

项目摘要 大脑的多巴胺能和血清素能系统与许多精神病疾病有关 成瘾和抑郁。但是，关于这些系统的投资较少 动态互动以调节早期不良事件后的动机变化以及它们如何 调节响应导致功能的恢复和增益。例如，临床和临床前发现 暴露于外源性大麻素（例如Δ9-四氢大麻酚）（THC，主要精神活性） 大麻的成分）在青少年期间，导致动机缺陷与压力相似 与受损的情感状态（例如抑郁症）一致的。激动的初步工作 实验室表明5-羟色胺（5HT）释放在腹侧盖区（VTA）激发多巴胺（DA）中 神经元，增强了伏隔核（NAC）中的阶段DA释放，并正在加强。我们的初步数据 还表明，青少年四氢大麻酚的潜在反动机作用可能是由于下降而引起的 由CB1受体在VTA中从5HT终端中释放神经递质释放的概率 这些轴突。在这里，我们提出了两个实验，以研究CB1受体在5HT上的功能作用 VTA中的终端。首先，我们将通过Cre-Lox重组方法控制CB1受体表达 涉及细胞类型的功能和救援的特异性损失，以隔离CB1受体在VTA 5HT上的作用 探测与提示相关的多巴胺能编码融合行为的终端（AIM 1）。接下来，我们将确定是否 慢性青少年暴露于THC可减少动机及其多巴胺能在成年和 这些不良适应作用是否需要在VTA中的5HT末端表达的CB1受体（AIM 2）。这 目前的研究将结合行为，解剖学，电生理学，快速扫描循环的组合 伏安法，病毒介导的基因转移和光遗传学。此外，实验将包括男性和 女性将在成年动物中复制。 5HT传入的CB1受体的特定遗传控制 VTA DA神经元和该电路的光遗传学审查将允许对当前假设进行明确检验 内源性大麻素在动机中的功能及其功能障碍的后果 青少年。通过研究5HT终端/DA与CB1接收器信号的相互作用，目前 提案利用尚未适用于这些问题的工具来应对NIDA的使命并产生 对治疗条件的理论策略的新见解涉及动机。