Enduring Consequences of Adolescent Cannabinoid and Methylphenidate Exposure

项目摘要 青少年使用大麻是一个突出的公共卫生问题。事实上，接触大麻期间， 青春期是一个以冲动为特征的发展时期，与适应不良的决定有关 在成年期制作。全国对大麻使用态度的变化以及由此产生的对大麻改革的推动， 大麻法律（21个州和哥伦比亚特区目前已经以某种形式使大麻合法化） 强调需要研究大麻素暴露的长期神经生物学后果。同样地， 哌醋甲酯（MPH，利他林®）处方，一种精神兴奋剂，主要用于冲动的青少年， 已经显著上升，因此与大麻的共同接触现在比以往任何时候都更有可能发生。 考虑到MPH与大麻激活的相同神经基质相互作用， 暴露于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，这是冲动控制受损的基础， 处理。我们将首先确定青春期冲动表型之前，药物治疗， 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 冲动型和控制型动物之间的区别接下来，实时多巴胺（DA）释放和脑内放电模式 在精确的行为时期观察到的，将在光遗传学期间用专门的传感器表征。 在青春期暴露于THC的成年动物中的延迟折扣任务（目的1）。重要的是，THC的影响 青少年期的治疗将与成人接触后的治疗进行对比。在目标2中， 研究青春期THC治疗如何改变eCB信号传导，以及这些改变是否 作为冲动表型和暴露年龄的函数的变化。目标3将以前两个目标为基础， 确定THC和MPH共同暴露对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。创新的互补使用 记录方法有可能阐明DA神经传递的神经机制的变化， 大脑活动模式可能解释成年人暴露于以下物质后冲动控制的差异： 大麻和/或利他林。拟议的实验响应PA-14-163，“ 大麻使用和大麻素对发育中的大脑”，通过检查行为，神经化学和 eCB信号传导的电生理介导，支配中脑边缘DA加工的动态控制， 冲动控制及其潜在的功能障碍，暴露于THC，MPH或其组合， 青春期

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.