Neurodevelopmental Effects of Adolescent Cannabis Use

描述(由申请人提供)： 在青春期使用大麻通常早于在晚年使用海洛因等“重”毒品，这引发了人们对大麻可能的“门户”效应的猜测。与药物有关的环境和固有的个体差异(如冲动、多动)等因素，在早期使用药物之前，可能会影响青春期的神经发育，似乎增加了药物滥用障碍的风险。中皮质边缘系统(MCLS)在情绪调节、奖赏和动机等方面起重要作用，并表达大量的大麻素受体(CB1)。我们观察到，暴露于大麻的人胎儿杏仁核多巴胺(DA)相关基因表达受损，杏仁核是MCL的一个组成部分(还包括伏隔核(NAcc)、腹侧被盖区(VTA)和内侧前额叶皮质(MPFC))。此外，我们发现，服用THC(大麻的精神活性成分)的青春期大鼠在成年后增加了海洛因的摄入量，这表明大麻素和阿片系统之间存在联系。这项建议的目的是确定MCLs结构中的神经生物学变化，以解释青春期暴露于THC对成年后海洛因自我给药的影响。在体内，将研究青春期暴露于THC的成年大鼠MCLs结构中与CB1、阿片神经肽和DA神经系统相关的DA水平以及基因表达和受体结合。还将评估风险因素的影响，如行为个体差异(例如，高行为活动、高冲动)和暴露于THC的环境背景，以了解它们对海洛因自我给药行为和神经生物学的影响。这些研究应提供信息，说明在发育过程中是否存在THC暴露的长期影响，以证实神经生物学“门户”假说，如果存在，则有助于确定青少年中可能影响成年后海洛因滥用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.