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

项目总结 大脑的多巴胺和5-羟色胺能系统与许多精神疾病有关，包括 上瘾和抑郁。然而，关于这些系统是如何 动态相互作用，以调节早期生活中不良事件后动机的变化，以及它们是如何 调节导致功能恢复和获得的反应。例如，临床和临床前研究结果 接触外源性大麻素，如Δ9-四氢大麻酚(主要精神活性物质 在青春期)，会导致类似于压力引起的动机缺陷 这与抑郁等情感状态的折衷是一致的。令人兴奋的前期工作来自我们的 实验室研究表明，腹侧被盖区(VTA)释放5-羟色胺(5-HT)兴奋多巴胺(DA)。 神经元，促进伏核(NAC)中DA的时相释放，并正在加强。我们的初步数据 这也表明，青少年THC的潜在反动机效应可能来自于 CB1受体激活引起VTA内5HT终末神经递质释放的可能性 这些轴突。在这里，我们提出两个实验来研究CB1受体在5-羟色胺中的功能作用 VTA中的终端。首先，我们将通过cre-lox重组途径控制cb1受体的表达。 涉及细胞类型特异性功能丧失和挽救以分离CB1受体在VTA 5HT中的作用 探索与线索相关的多巴胺能编码动机行为的终末(目标1)。接下来，我们将确定是否 青少年长期暴露于THC会降低动机及其与成年期和青少年的多巴胺能相关 这些不适应效应是否需要CB1受体在VTA的5-羟色胺终末表达(目标2)。这个 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，实验将包括雄性和 雌性，并将在成年动物身上复制。5-羟色胺传入细胞上CB1受体的特异性遗传控制 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作用及暴露后其功能障碍的后果 青春期。因此，通过研究5-羟色胺末端/DA与CB1受体信号的相互作用，目前 Proposal利用尚未应用于这些问题的工具来回应NIDA的使命并生成 对治疗动机受损的疾病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.