Enduring Consequences of Adolescent Cannabinoid and Methylphenidate Exposure

项目总结 青少年吸食大麻是一个突出的公共卫生问题。事实上，在过去的几年里接触大麻 青春期，一个以冲动为特征的发展时期，与不适应的决定有关 成年后制作的。国民对大麻使用态度的变化以及由此而推动的大麻改革 大麻法律(21个州和哥伦比亚特区目前已将某种形式的大麻合法化) 强调有必要审查大麻素暴露的长期神经生物学后果。同样， 哌醋甲酯(MPH，利他林®)处方，一种对冲动的青少年经常开出的精神刺激剂， 显著上升，因此与大麻共同接触的可能性比以往任何时候都更大。 鉴于mph与大麻激活的相同神经底物相互作用，问题是 接触四氢大麻酚(大麻中的主要精神活性成分)、公共卫生小时数或其组合 青春期促进持久的神经适应，潜在的折衷冲动控制需要 地址。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 腹侧被盖区多巴胺能神经元对内源性大麻素(ECB)的动员不同 在冲动和受控的动物之间。接下来，实时多巴胺(DA)释放和伏隔放电模式 在精确的行为时期观察到的，将在 青春期暴露于THC的成年动物的延迟折扣任务(目标1)。重要的是，THC的影响 青春期的治疗将与成人暴露后的治疗形成对比。在《目标2》中我们将 研究青春期使用THC治疗如何修改ECB信号，以及这些修改是否 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共同暴露对ECB信号和多巴胺能编码的影响 与单独使用这两种药物相比，他们的决策能力更强。创新的互补使用 记录方法可能阐明支配DA神经传递和 伏隔活动模式可能解释暴露于铅的成年后冲动控制的差异 青春期吸食大麻和/或利他林。建议的实验响应PA-14-163，“效果 大麻的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信号调控脑内中脑边缘DA加工的电生理调节 接触THC、MPH或其组合后的脉冲控制及其潜在功能障碍 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.