The Effects of Cannabis Use/Abuse on In Vivo Dopamine Function

在美国，超过6%的12岁以上的人在过去的一个月里使用过大麻，这种物质占该国非法药物使用的大约55%。认为大麻是一种“安全”的非法药物，没有长期不良后果，这可能导致大麻的使用率高于“硬性”药物。然而，探索大麻神经生物学效应的脑成像研究相对较少。关于大麻使用的两个主要领域，都可能与多巴胺（DA）系统有关，突出了进一步研究大麻使用者DA功能的体内人脑成像研究的重要性。首先，已观察到病前使用大麻与精神分裂症之间存在相对较强的关联（优势比> 2），特别是在青少年使用大麻时。在精神分裂症中，在受体成像研究中已经观察到DA系统的异常。鉴于青少年使用大麻与精神分裂症之间的流行病学联系，对使用/滥用大麻的个人进行这种性质的神经受体成像研究特别令人感兴趣。其次，早期使用大麻被认为是今后使用硬性毒品的一个风险因素。这被称为“网关”假说和神经生物学因素，如敏化可能发挥作用。致敏是指在重复和慢性暴露于滥用药物后，在丘脑核（NAc）的奖赏通路中发生的增强的DA反应。如果暴露于大麻可诱导对其他滥用药物的交叉致敏（即先前暴露于大麻导致随后暴露于另一类药物时NAc中DA释放增加），则这将支持网关效应。本申请旨在研究从青少年开始的重复大麻暴露对腹侧纹状体（VST）奖励系统（包括NAc的区域）内体内DA传输的影响。这将通过正电子发射断层扫描（PET）来完成，方法是测量8名从青春期开始重复使用大麻的成年人和8名匹配对照者中安非他明诱导的[11 C]雷氯必利置换。如果我们试图检验的假设得到证实--即从青春期开始吸食大麻会改变以后生活中纹状体中的多巴胺信号--这将为大麻与精神分裂症之间的流行病学联系提供强有力的神经生物学基础，对大麻作为入门药物的理论产生影响，并加强大麻使用不能被视为“安全”滥用药物的论点。在美国，超过6%的12岁以上的人在过去的一个月里使用过大麻，这种物质占该国非法药物使用的大约55%。然而，探索大麻神经生物学效应的脑成像研究相对较少。如果我们试图验证的假设得到证实--即从青春期开始吸食大麻会改变日后大脑中的多巴胺奖赏信号--这将为大麻与精神分裂症之间的流行病学联系提供强有力的神经生物学基础，对大麻作为入门药物的理论产生影响，并加强大麻使用不能被视为“安全”滥用药物的论点。

DESCRIPTION (provided by applicant): In the United States over 6% of individuals greater than 12 years old have used marijuana in the past month and this substance accounts for approximately 55% of the illicit drug use in this country. The perception that cannabis is a "safe" illicit drug, without long-term adverse consequences, may contribute to the higher rates of use of marijuana when compared with more "hard" drugs. However, there has been relatively few brain imaging studies exploring the neurobiological effects of cannabis. Two main areas of recent interest with regards to cannabis use, both potentially related to the dopamine (DA) system, highlight the importance of further in vivo human brain imaging studies examining DA function in cannabis users. First, a relatively strong association (odds ratio > 2) between premorbid cannabis use and schizophrenia has been observed, particularly when cannabis use occurs in adolescence. In schizophrenia, abnormalities of the DA system have been observed in receptor imaging studies. Given the epidemiological link between cannabis use in adolescence and schizophrenia a neuroreceptor imaging study of this nature in individuals who use/abuse cannabis is of particular interest. Second, early use of cannabis has been considered a risk factor for the future use of hard drugs. This has been termed the "gateway" hypothesis and neurobiological factors such as sensitization may play a role. Sensitization refers to the enhanced DA response in the reward pathway of the nucleus accumbens (NAc) that occurs following repeated and chronic exposure to drugs of abuse. If exposure to cannabis can induce a cross- sensitization to other drugs of abuse (i.e. prior exposure to cannabis results in an increased DA release in the NAc on subsequent exposure to another class of drugs) this would be supportive of the gateway effect. This application seeks to examine the effects of repeated cannabis exposure, beginning in adolescent, on DA transmission in vivo within reward system of the ventral striatum (VST), an area which includes the NAc,. This will be accomplished with positron emission tomography (PET) by measuring amphetamine-induced displacement of [11C]raclopride in 8 adult individuals with a history of repeated cannabis use beginning in adolescence and 8 matched controls. If the hypothesis we seek to test is confirmed - that marijuana use beginning in adolescence alters dopamine signaling in the striatum later in life - it would provide a strong neurobiological basis for the epidemiological link between this drug and schizophrenia, have implications for the theory that marijuana serves as a gateway drug, and strengthen the argument that marijuana use cannot be considered a "safe" drug of abuse. In the United States over 6% of individuals greater than 12 years old have used marijuana in the past month and this substance accounts for approximately 55% of the illicit drug use in this country. However, there has been relatively few brain imaging studies exploring the neurobiological effects of cannabis. If the hypothesis we seek to test is confirmed - that marijuana use beginning in adolescence alters dopamine reward signaling in the brain later in life - it would provide a strong neurobiological basis for the epidemiological link between this drug and schizophrenia, have implications for the theory that marijuana serves as a gateway drug, and strengthen the argument that marijuana use cannot be considered a "safe" drug of abuse.