Neurodevelopmental Effects of Adolescent Cannabis Use

描述（由申请人提供）： 在青少年时期使用大麻通常早于在以后的生活中使用海洛因等“重”毒品，这引起了人们对大麻可能的“门户”效应的猜测。与药物相关的环境和固有的个体差异等因素（例如，冲动、多动），早于早期吸毒，可影响青春期的神经发育，似乎会增加药物滥用障碍的风险。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）。 我们已经观察到，暴露于大麻的人类胎儿在杏仁核中的多巴胺（DA）相关基因表达受损，杏仁核是MCLS的一个组成部分（还包括延髓核（NAcc），腹侧被盖区（VTA）和内侧前额叶皮层（mPFC））。此外，我们发现，服用THC（大麻的精神活性成分）的青少年大鼠成年后海洛因摄入量增加，这表明大麻素和阿片系统之间存在联系。本提案的目的是确定MCLS结构中的神经生物学改变，这些改变可以解释青少年时期THC暴露对成年期海洛因自我管理的影响。体内DA水平以及与CB1，阿片类神经肽和DA神经系统相关的基因表达和受体结合将在青春期暴露于THC的成年大鼠的MCLS结构中进行研究。风险因素的影响，如行为个体差异（例如，高行为活动性、高冲动性）和接触THC的环境背景对海洛因自我给药行为和神经生物学的影响也将进行评估。这些研究应提供资料，说明在发育过程中接触THC是否存在长期影响，以证实神经生物学“关口”假说，如果是，则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。

DESCRIPTION (provided by applicant): 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 (the psychoactive 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.