Neurodevelopmental Effects of THC on The VTA Dopamine System and Behavior

项目摘要 避孕药是孕妇使用的最常见的非法药物。长期疗效的临床研究 怀孕期间吸食大麻对后代的认知发育有不利影响 从童年早期一直到晚年。事实上，儿童和青少年接触到精神活性成分 大麻，Δ9-四氢大麻酚（THC），在出生前显示注意力，学习和问题减少 解决问题、多动、冲动和冒险行为增加。因此，早期暴露于 THC可能会诱导持久的适应，包括大脑奖励多巴胺（DA）系统，导致 适应不良行为，从情感失调到成瘾脆弱性。然而，临床前 令人惊讶的是，关于大麻使用对大脑奖励途径发展的影响的研究非常缺乏。 因此，迫切需要鉴定分子底物和有效的预防和治疗策略。 治疗这些可能使个人脆弱的有害影响。在此，我们提出三个 实验来测试我们的总体假设，产前THC暴露诱导加强传入 腹侧被盖区（VTA）DA神经元上的兴奋性突触，连同异常的 内源性大麻素（ECB）系统功能，诱导持续兴奋驱动DA神经元的基础上， 饮酒的风险表型。首先，我们将确定产前THC暴露是否会导致加强 兴奋性传递到腹侧被盖区DA细胞，我们将检查ECB的病理重组 系统的分子机械与纳米级精度（目标1）。接下来，我们将测试THC的后代- 暴露的母鼠表现出对自然回报的敏感性增加，对酒精依赖的脆弱性增加， 通过生物化学和行为读数（目标2）的成年期。最后，我们将探讨一个产后 药物干预，以扭转产前暴露于THC的有害影响（目标3）。对我们 知识，这些研究问题从来没有在这种多学科的方式具体解决。 我们将测试我们的假设，通过暴露大鼠母鼠在怀孕期间THC和结合体外 电生理记录、药理学操作、神经化学检测方案沿着 先进的随机光学重建显微镜（STORM）超分辨率成像和行为 四氢大麻酚处理水坝后代的范例。我们将利用协调的专业知识， 多个实验室，我们将确保研究将平行进行，而不是在一个单一的串行 实验室这将通过国际合作研究促进科学知识的进步， 将同时影响三个不同国家的公众意识和决策者。

PROJECT SUMMARY Marijuana is the most common illicit drug used by pregnant women. Clinical studies on the long-term effects of marijuana smoking during pregnancy show its detrimental impact on the cognitive development of the offspring from early childhood until later in life. In fact, children and adolescents exposed to the psychoactive ingredient of marijuana, Δ9-tetrahydrocannabinol (THC), before birth display reduced attention, learning and problem solving, hyperactivity, increased impulsivity and engagement in risk-taking behaviors. Hence, early exposure to THC might induce enduring adaptations encompassing the brain reward dopamine (DA) system resulting in maladaptive behavior, ranging from affective dysregulation to addiction vulnerability. However, preclinical studies on the impact of marijuana use on the development of brain reward pathways are surprisingly lacking. Hence, there is an urgent need to identify molecular substrates and effective strategies for prevention and treatment of these detrimental effects that might confer individual vulnerability. Here, we propose three experiments to test our overarching hypothesis that prenatal THC exposure induces a strengthening at afferent excitatory synapses on ventral tegmental area (VTA) DA neurons, which together with abnormal endocannabinoid (ECB) system function, induces a persistent excitatory drive to DA neurons underlying an at- risk phenotype for alcohol seeking. First, we will determine if prenatal THC exposure leads to strengthening of excitatory transmission onto VTA DA cells and we will examine the pathological reorganization of the ECB system's molecular machinery with nanoscale precision (Aim 1). Next, we will test whether offspring of THC- exposed dams display increased sensitivity to natural rewards and vulnerability to alcohol dependence in adulthood by means of biochemical and behavioral readouts (Aim 2). Finally, we will explore a postnatal pharmacological intervention to reverse the deleterious effects of prenatal exposure to THC (Aim 3). To our knowledge, these research issues have never been specifically addressed in this multi-disciplinary manner. We will test our hypothesis by exposing rat dams to THC during pregnancy and by combining ex vivo electrophysiological recordings, pharmacological manipulations, neurochemical detection schemes along with sophisticated Stochastic Optical Reconstruction Microscopy (STORM) super-resolution imaging and behavioral paradigms in the offspring of THC-treated dams. We will take advantage of the coordinated expertise of multiple laboratories and we will ensure that studies will be carried out in parallel rather than serially in a single laboratory. This will lead to an advance of scientific knowledge through international collaborative research that will simultaneously impact public awareness and policy makers of three different countries.