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: 10162575
• 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 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10162575
• 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; 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.

项目摘要 大麻是孕妇使用的最常见的非法药物。关于长期影响的临床研究 怀孕期间吸烟大麻对后代的认知发展有害 从童年到生命的早期。实际上，暴露于精神活性成分的儿童和青少年 大麻，δ9-四氢大麻酚（THC），出生之前的注意力减少了注意力，学习和问题 解决，多动症，冲动性和参与冒险行为的参与。因此，早期接触 THC可能引起持久的适应，包括大脑奖励多巴胺（DA）系统，导致 适应不良的行为，从情感失调到成瘾脆弱性。但是，临床前 令人惊讶地缺乏有关大麻使用对大脑奖励途径发展的影响的研究。 因此，迫切需要确定分子底物和预防和 治疗这些有害影响可能会带来个体脆弱性。在这里，我们建议三个 测试我们总体假设的实验，即产前THC暴露会引起情感的增强 腹侧对盖区域（VTA）DA神经元的兴奋性突触，与异常一起 内源性大麻素（欧洲央行）系统功能，引起了持续的兴奋动力 寻求酒精的风险表型。首先，我们将确定产前THC是否导致加强 兴奋性传播到VTA DA细胞上，我们将检查欧洲央行的病理重组 具有纳米级精度的系统的分子机械（AIM 1）。接下来，我们将测试THC的后代 - 暴露的大坝表现出对自然奖励的敏感性和对酒精依赖的脆弱性的敏感性 通过生化和行为读数成年（AIM 2）。最后，我们将探索产后 药理干预措施扭转了产前暴露于THC的有害影响（AIM 3）。向我们 知识，这些研究问题从未以这种多学科方式专门解决。 我们将通过在怀孕期间将大鼠大坝暴露于THC和结合体内来检验我们的假设 电生理记录，药物操纵，神经化学检测方案以及 复杂的随机光学重建显微镜（Storm）超分辨率成像和行为 THC处理的大坝后代的范例。我们将利用协调的专业知识 多个实验室，我们将确保将研究并行进行，而不是在一个单一的单一中进行 实验室。这将通过国际合作研究导致科学知识的进步， 只会影响三个不同国家的公众意识和政策制定者。