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: 9193888
• 负责人: Joseph F Cheer
• 金额: $ 39.87万
• 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/9193888
• 关键词: Address; Adolescence; Adolescent; Adolescent marijuana use; Adult; Aftercare; Age; Animals; Attention deficit hyperactivity disorder; Attitude; Behavioral; Brain; Cannabinoids; Clinical; Control Animal; 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; Lead; Link; Literature; Long-Term Effects; Marijuana; Marijuana Dependence; Measures; Mediating; Mediation; Medical Marijuana; Mental disorders; Methods; Methylphenidate; Microdialysis; Modification; Monitor; Motivation; National Institute of Drug Abuse; Neurobiology; Pattern; Pharmaceutical Preparations; Pharmacological Treatment; Phenotype; Plasma; Policies; Population; Populations at Risk; Process; Public Health; Public Opinion; Rattus; Regulation; Reporting; Ritalin; Scheme; Staging; Subgroup; Synaptic Transmission; THC exposure; Task Performances; Testing; Therapeutic; Time; Ventral Tegmental Area; Work; addiction; adolescent patient; base; comparative; design; discounting; dopaminergic neuron; endocannabinoid signaling; experience; innovation; marijuana legalization; marijuana use; marijuana user; mature animal; neural correlate; neuroadaptation; neurobiological mechanism; neurochemistry; neuromechanism; neurotransmission; psychostimulant; relating to nervous system; research study; sensor; tool; trait; 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.

项目摘要 青少年大麻使用是一个杰出的公共卫生问题。确实，在 青少年是以冲动性为特征的发育期，与适应不良的决策相关 成年。不断变化的国家使用大麻的参与者以及由此产生的推动改革 大麻法（21个州和哥伦比亚特区目前以某种形式使大麻合法化） 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，一种高度开处方的精神刺激，是冲动的青少年， 现在，与大麻的共同暴露相比，与以往任何时候都更有可能发生。 鉴于MPH与大麻激活的相同神经底物相互作用，因此是否存在问题 暴露于THC（大麻中的主要精神活性成分），MPH或它们的组合 青少年促进持久的神经适应受损的冲动控制需要 解决。我们将首先在药物处理之前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是否 内源性大麻素（欧洲央行）动员腹侧对段区域（VTA）不同的动员 在冲动和受控动物之间。接下来，实时多巴胺（DA）释放和伏托射击方式 在精确的行为时期观察到，将在A期间用专用传感器进行吻合表征 在青春期中暴露于THC的成年动物中的延迟订立任务（AIM 1）。重要的是，THC的影响 青少年的治疗将与成人暴露后发生的患者形成鲜明对比。在目标2中，我们将 检查青少年修饰符中的THC处理欧洲央行信号传导以及这些修改如何 变化是冲动表型和暴露年龄的函数。 AIM 3将基于前两个目标 确定THC和MPH共曝光对欧洲央行信号传导和多巴胺能编码的影响是否存在 与仅两种药物的决策相比，决策更大。创新的完整使用 记录方法可能会阐明管理DA神经传递和 暴露后，在成年期内可能解释了冲动控制的差异的背活动模式 青少年大麻和/或利他林。提出的实验对PA-14-163做出了回应： 通过检查行为，神经化学和 欧洲央行信号传导的电生理调解，控制中左右DA处理的动态控制 暴露于THC，MPH或它们的组合后，冲动控制及其潜在的功能障碍 青少年。