Neurodevelopmental Effects of THC on The VTA Dopamine System and Behavior

THC 对 VTA 多巴胺系统和行为的神经发育影响

• 批准号: 10404984
• 负责人: Joseph F Cheer
• 金额: $ 33.51万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-30 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10404984
• 关键词: Acute; Address; Adolescent; Adult; Affect; Affective; Alcohol Phenotype; Alcohol consumption; Alcohol dependence; Alcohols; Animals; Attention; Attenuated; Awareness; Behavior; Behavioral; Behavioral Paradigm; Biochemical; Birth; Brain; CNR1 gene; Cells; Child; Clinical Research; Cognitive; Country; Cues; Data; Detection; Development; Dopamine; Electrophysiology (science); Emotions; Endocannabinoids; Ensure; Enzymes; Excitatory Synapse; Exposure to; Female; Glutamates; Goals; High Prevalence; Human; Hyperactivity; Image; Impairment; Impulsivity; Individual; Inhibitory Synapse; International; Intervention; Knowledge; Laboratories; Learning; Life; Long-Term Effects; Marijuana; Marijuana Abuse; Marijuana Dependence; Measures; Microscopy; Molecular; Optics; Pathologic; Pathway interactions; Pharmacological Treatment; Pharmacology; Phenotype; Policy Maker; Pregnancy; Pregnant Women; Pregnenolone; Prevalence; Prevention; Prevention strategy; Problem Solving; Psychological reinforcement; Public Policy; Rattus; Regulation; Research; Resolution; Rewards; Risk; Risk-Taking; Role; Scheme; Scientific Advances and Accomplishments; Slice; Synapses; Synaptic Transmission; THC exposure; Testing; Tetrahydrocannabinol; Ventral Tegmental Area; addiction; alcohol risk; alcohol seeking behavior; base; cell type; cognitive development; cognitive function; dopamine system; dopaminergic neuron; early childhood; endocannabinoid signaling; endogenous cannabinoid system; evidence base; experimental study; fetal marijuana exposure; illicit drug use; in utero; insight; maladaptive behavior; male; marijuana smoking during pregnancy; marijuana use; maternal marijuana exposure; mature animal; motivated behavior; multidisciplinary; nanoscale; neurochemistry; neurodevelopmental effect; novel; offspring; postnatal; preclinical study; prenatal; prenatal exposure; prevent; reconstruction; relating to nervous system; reward processing; steroid hormone; transmission process

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.

项目概要 大麻是孕妇最常见的非法药物。长期影响的临床研究 怀孕期间吸食大麻对后代认知发展有不利影响 从幼儿期一直到晚年。事实上，接触精神活性成分的儿童和青少年 出生前吸食大麻、Δ9-四氢大麻酚 (THC) 会导致注意力、学习能力和问题减少 解决问题、多动、冲动增加和参与冒险行为。因此，尽早接触 THC 可能会诱导大脑奖励多巴胺 (DA) 系统的持久适应，从而导致 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，关于吸食大麻对大脑奖赏通路发育影响的研究却非常缺乏。 因此，迫切需要确定分子底物和有效的预防和治疗策略。 处理这些可能导致个人脆弱性的有害影响。在此，我们提出三点建议 实验来检验我们的总体假设，即产前 THC 暴露会导致传入神经增强 腹侧被盖区 (VTA) DA 神经元的兴奋性突触，以及异常 内源性大麻素 (ECB) 系统功能，诱导对 DA 神经元的持续兴奋驱动 寻求酒精的风险表型。首先，我们将确定产前 THC 暴露是否会导致强化 兴奋性传输到 VTA DA 细胞，我们将检查 ECB 的病理重组 系统的分子机械具有纳米级精度（目标 1）。接下来，我们将测试 THC 的后代是否- 暴露的水坝表现出对自然奖励的敏感性增加以及对酒精依赖的脆弱性 通过生化和行为读数来了解成年期（目标 2）。最后，我们将探索产后 药物干预，以扭转产前接触 THC 的有害影响（目标 3）。致我们的 知识，这些研究问题从未以这种多学科的方式得到具体解决。 我们将通过在怀孕期间将大鼠暴露于 THC 并结合离体来检验我们的假设 电生理记录、药理学操作、神经化学检测方案以及 先进的随机光学重建显微镜（STORM）超分辨率成像和行为 经过 THC 处理的水坝后代的范例。我们将利用协调的专业知识 多个实验室，我们将确保研究将并行进行，而不是在一个单一的实验室中连续进行 实验室。这将通过国际合作研究推动科学知识的进步 将同时影响三个不同国家的公众意识和政策制定者。