Neurodevelopmental Effects of Adolescent Cannabis Use

在青春期使用大麻（cannabis sativa）通常早于使用“重”毒品，如 海洛因在以后的生活中，这引起了人们对大麻可能的“门户”效应的猜测。等因素 由于药物相关的环境和固有的个体差异（例如，冲动、多动）， 早于早期药物使用，可以影响青春期的神经发育，似乎增加了 物质滥用障碍的风险。中皮质边缘系统（MCLS）主要参与，例如， 情绪调节，奖励和动机，并表达显着水平的大麻素受体（CB1）。 我们观察到，暴露于大麻的人类胎儿的多巴胺（DA）相关基因受损， 在杏仁核中表达，杏仁核是MCLS的一个组成部分（也包括杏仁核（NAcc）， 腹侧被盖区（VTA）和内侧前额叶皮质（mPFC））。此外，我们发现，青少年 服用THC（大麻的精神活性成分）的大鼠成年后海洛因摄入量增加 表明大麻素和阿片系统之间存在联系本提案的目标是确定 MCLS结构的神经生物学改变可以解释THC暴露的影响， 青少年在成年后自我服用海洛因。体内DA水平以及基因表达和 将在MCLS中研究与CB1、阿片类神经肽和DA神经系统相关的受体结合 在青春期暴露于THC的成年大鼠的结构。风险因素的影响，如行为 个体差异（例如，高行为活动，高冲动）和THC的环境背景 还将评估暴露对海洛因自我给药行为的影响， 神经生物学这些研究应提供数据，说明THC是否存在长期影响 暴露在发展过程中，以证实神经生物学的“网关”假说，如果是这样，有助于 确定青少年中可能影响成年后滥用海洛因风险的潜在风险因素。

Marijuana (cannabis sativa) use during adolescence normally predates the use of "heavy" drugs such as heroin in later life which has raised speculations as to possible "gateway" effects of marijuana. Factors such as drug-associated environment and inherent individual differences (e.g., impulsivity, hyperactivity), which predates early drug use and can influence neurodevelopment during adolescence, appear to increase the risk for substance abuse disorders. The mesocorticolimbic system (MCLS) is critically involved in, e.g., emotional regulation, reward, and motivation and express significant levels of cannabinoid receptors (CB1). We have observed that cannabis-exposed human fetuses have impaired dopamine (DA)-related gene expression in the amygdala, a component of the MCLS (which also includes the nucleus accumbens (NAcc), ventral tegmental area (VTA), and medial prefrontal cortex (mPFC)). Moreover, we found that adolescent rats administered THC (thepsychoactive component of cannabis) have increased heroin intake in adulthood suggesting a link between the cannabinoid and opioid systems. It is the goal of this proposal to identify neurobiological alterations in MCLS structures that can account for the effects of THC exposure during adolescence on heroin self-administration in adulthood. In vivo DA levels as well as gene expression and receptor binding linked to the CB1, opioid neuropeptides, and DA neural systems will be studied in MCLS structures in adult rats exposed to THC during adolescence. The impact of risk factors such as behavioral individual differences (e.g., high behavioral activity, high impulsivity) and the environmental context of THC exposure will also be evaluated in regard to their influence on heroin self-administration behavior and neurobiology. These studies should provide information as to whether there exist a long-term impact of THC exposure during development to substantiate a neurobiological "gateway" hypothesis and, if so, help to identify potential risk factors in adolescents that can influence the risk for heroin abuse in adulthood.