Enduring Consequences of Adolescent Cannabinoid and Methylphenidate Exposure

青少年接触大麻素和哌甲酯的持久后果

• 批准号: 9472305
• 负责人: Joseph F Cheer
• 金额: $ 40.72万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9472305
• 关键词: Address; Adolescence; Adolescent; Adolescent marijuana use; Adult; Aftercare; Age; Animals; Attention deficit hyperactivity disorder; Attitude; Behavioral; Brain; Cannabinoids; Clinical; Crisis Intervention; Cues; Data; Decision Making; Detection; Development; Disease; District of Columbia; Dopamine; Dose; Electrophysiology (science); Endocannabinoids; Exhibits; Exposure to; Functional disorder; Funding; Future; Harm Reduction; High School Student; Human; Impulsivity; In Vitro; Incidence; Individual; Laws; Link; Literature; Long-Term Effects; Marijuana; Marijuana Dependence; Measures; Mediating; Mediation; Medical Marijuana; Mental disorders; Methods; Microdialysis; Modification; Monitor; Motivation; National Institute of Drug Abuse; Neurobiology; Pattern; Pharmaceutical Preparations; Pharmacological Treatment; Phenotype; Plasma; Policies; Population; Populations at Risk; Public Health; Public Opinion; Rattus; Regulation; Reporting; Ritalin; Scheme; Subgroup; Synaptic Transmission; THC exposure; Task Performances; Testing; Therapeutic; Time; Ventral Tegmental Area; Work; addiction; adolescent patient; base; comparative; design; discount; discounting; dopaminergic neuron; endocannabinoid signaling; experience; experimental study; innovation; marijuana legalization; marijuana use; marijuana user; mature animal; neural correlate; neuroadaptation; neurobiological mechanism; neurochemistry; neuromechanism; neurotransmission; optogenetics; psychostimulant; relating to nervous system; sensor; tool; trait impulsivity; transmission process; vulnerable adolescent

PROJECT SUMMARY Adolescent marijuana use is a prominent public health concern. Indeed, exposure to marijuana during adolescence, a developmental period characterized by impulsivity, is correlated with maladaptive decision making in adulthood. The changing national attitudes on marijuana use and the resultant push for the reform of marijuana laws (21 states and the District of Columbia currently have legalized marijuana in some form) highlight a need to examine the long-term neurobiological consequences of cannabinoid exposure. Likewise, methylphenidate (MPH, Ritalin®) prescription, a psychostimulant highly prescribed to impulsive adolescents, has significantly risen and therefore co-exposure with marijuana is now more likely to happen than ever before. Given that MPH interacts with the same neural substrates activated by marijuana, the question of whether exposure to THC (the main psychoactive component in marijuana), MPH, or their combination during adolescence promotes enduring neuroadaptations underlying compromised impulse control needs to be addressed. We will first define adolescent impulsivity phenotypes prior to pharmacological treatments and will utilize sophisticated microdialysis detection schemes and in vitro electrophysiology to determine whether endocannabinoid (eCB) mobilization from dopaminergic neurons of the ventral tegmental area (VTA) differs between impulsive and controlled animals. Next, real-time dopamine (DA) release and accumbal firing patterns observed at precise behavioral epochs, will be optogenetically characterized with a specialized sensor during a delay-discounting task in adult animals exposed to THC in adolescence (aim 1). Importantly, the effects of THC treatment in adolescence will be contrasted to those occurring following adult exposure. In aim 2 we will examine how treatment with THC in adolescence modifies eCB signaling and whether these modifications change as a function of impulsive phenotype and age of exposure. Aim 3 will build upon the prior two aims to determine if the effects of THC and MPH co-exposure on eCB signaling and dopaminergic encoding of decision making are greater compared to those of either drug alone. The complementary use of innovative recording methods is likely to elucidate changes in neural mechanisms governing DA neurotransmission and accumbal activity patterns that may explain differences in impulse control in adulthood following exposure to marijuana and/or Ritalin in adolescence. The proposed experiments respond to PA-14-163, “Effects of Cannabis Use and Cannabinoids on the Developing Brain” by examining the behavioral, neurochemical and electrophysiological mediation of eCB signaling governing the dynamic control of mesolimbic DA processing in impulse control and its potential dysfunction following exposure to THC, MPH, or their combination in adolescence.

项目概要 青少年吸食大麻是一个突出的公共卫生问题。事实上，在吸食大麻期间 青春期是一个以冲动为特征的发展时期，与适应不良的决策相关 成年后制作。国民对大麻使用态度的变化以及由此推动的改革 大麻法（21 个州和哥伦比亚特区目前已以某种形式将大麻合法化） 强调需要检查大麻素暴露的长期神经生物学后果。同样地， 哌醋甲酯（MPH，Ritalin®）处方，一种高度为冲动青少年开出的精神兴奋剂， 显着上升，因此现在比以往任何时候都更有可能同时接触大麻。 鉴于 MPH 与大麻激活的相同神经底物相互作用，是否存在以下问题： 在吸食大麻期间接触 THC（大麻中的主要精神活性成分）、MPH 或其组合 青春期促进持久的神经适应，而这背后的冲动控制受损需要 已解决。在药物治疗之前，我们将首先定义青少年冲动表型，并将 利用复杂的微透析检测方案和体外电生理学来确定是否 腹侧被盖区 (VTA) 多巴胺能神经元的内源性大麻素 (eCB) 动员不同 冲动动物和受控动物之间。接下来，实时多巴胺 (DA) 释放和累积放电模式 在精确的行为时期观察到的，将在一个特定的过程中用专门的传感器进行光遗传学表征 对青春期接触 THC 的成年动物进行延迟贴现任务（目标 1）。重要的是，THC 的影响 青春期的治疗将与成人接触后发生的治疗形成对比。在目标 2 中，我们将 检查青春期 THC 治疗如何改变 eCB 信号传导以及这些改变是否 随着冲动表型和暴露年龄的变化而变化。目标 3 将建立在前两个目标的基础上 确定 THC 和 MPH 共同暴露是否对 eCB 信号传导和多巴胺能编码的影响 与单独使用任何一种药物相比，决策能力更强。创新的互补运用 记录方法可能会阐明控制 DA 神经传递和神经机制的变化 累积活动模式可以解释成年后暴露于环境后冲动控制的差异 青春期吸食大麻和/或利他林。拟议的实验响应 PA-14-163，“ 大麻的使用和大麻素对大脑发育的影响”，通过检查行为、神经化学和 eCB 信号的电生理介导控制中脑边缘 DA 处理的动态控制 暴露于 THC、MPH 或其组合后的冲动控制及其潜在功能障碍 青春期。