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

项目概要 大脑的多巴胺能和血清素能系统与许多精神疾病有关，包括 成瘾和抑郁。然而，关于这些系统如何 动态地相互作用以调节早年不良事件后动机的变化以及它们如何 调节导致恢复和功能获得的反应。例如，临床和临床前发现 接触外源性大麻素，例如 Δ9-四氢大麻酚（THC，主要的精神活性物质） 大麻的成分）在青春期会导致类似于压力引起的动机缺陷 这与抑郁症等情感受损状态一致。我们的令人兴奋的初步工作 实验室表明，腹侧被盖区 (VTA) 的血清素 (5HT) 释放会激发多巴胺 (DA) 神经元，增强伏隔核 (NAc) 中的阶段性 DA 释放，并且具有增强作用。我们的初步数据 还表明，青少年 THC 的潜在反动机作用可能是由于 由 CB1 受体激活引起的 VTA 5HT 末端释放神经递质的概率 这些轴突。在这里，我们提出两个实验来研究 CB1 受体对 5HT 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 涉及细胞类型特异性功能丧失和救援以分离 CB1 受体对 VTA 5HT 的作用 探测动机行为的线索相关多巴胺能编码的终端（目标 1）。接下来，我们将确定是否 青少年长期接触四氢大麻酚会降低动机及其与成年期和成年期的多巴胺能相关性 这些适应不良效应是否需要 VTA 中 5HT 末端表达的 CB1 受体（目标 2）。的 目前的研究将结合行为学、解剖学、电生理学、快速扫描循环 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 雌性并将在成年动物中复制。 CB1受体对5HT传入神经的特异性遗传控制 VTA DA 神经元和该电路的光遗传学询问，将允许对当前的假设进行明确的测试 内源性大麻素在动机中的功能及其在 THC 暴露后功能障碍的后果 青春期。因此，通过研究 5HT 末端/DA 与 CB1 受体信号传导的相互作用，目前 该提案利用尚未应用于这些问题的工具来响应 NIDA 的使命并产生 关于治疗动机受损病症的治疗策略的新见解。

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.