Genetic variation and marijuana's pharmacologic and cue-elicted effects

说明(申请人提供)：审查遗传变异性影响大麻依赖和使用大麻倾向的机制是一项高度优先的工作。然而，对于作为大麻依赖标志的候选表型的鉴定，人类研究很少。大麻素1型受体(CB1)是一种由CNR1基因编码的G偶联受体，它介导了大麻的精神活性和奖赏作用(Ledent等人，1999；Zhang等人，2004)。此外，有证据表明，脂肪酸氨基水解酶(FAAH)基因可能是一个重要的候选基因(Cravatt和Lichtman，2003)。CNR1的几个多态性和FAAH基因的一个与大麻依赖有关(Comes等人，1997年；Hopfer等人，2006年；Tyndale等人，2007年)，与大麻相关的中间表型，包括戒断和渴望(Heh等人，2008年)，以及积极的主观影响和生理刺激(Schacht等人，2008年)。尽管以前的发现具有启发性，但到目前为止还没有研究测试CNR1的变异性与与大麻相关的关键中间表型之间的关系，这些中间表型与大麻对急性影响的敏感性有关，例如增加积极的情感和奖励敏感性，减少消极的情感，以及主观刺激和醉酒。此外，在很大程度上还不清楚CNR1或FAAH变异是否与非戒断使用者的大麻欲望有关。这项先导性研究的主要目标是调查大麻急性和线索诱发效应中的可变性，这些效应与经验选择的CNR1和FAAH基因的多态有关。在一项2(基因)×2(药物管理：大麻加2.8%β-9-四氢大麻酚(THC)与大麻安慰剂；线索反应性：中性与大麻线索)的实验室研究中，我们将在80名高加索人不寻求治疗的重度大麻使用者中检查这些影响。CNR1和FAAH基因的基因分型将包括经验性选择的候选单核苷酸多态(SNPs)和标签SNPs。这项研究的长期目标是确定大麻效应的个体差异背后的遗传变异，这可能解释了个体对大麻依赖的敏感性差异。更好地了解这些机制可以为治疗大麻依赖的基因靶向药物治疗方法提供依据。 与公共健康相关：这项研究将有助于确定为什么一些使用大麻的人可能面临更大的滥用或依赖这种药物的风险。研究他们基因构成的个体差异将有助于揭示为什么这些人中的一些人可能对大麻的影响更敏感。这些信息可能对确定哪些人将从特定的大麻治疗中受益具有重要价值。

DESCRIPTION (provided by applicant): The examination of mechanisms by which genetic variability influences cannabis dependence and propensity to use marijuana is a high priority. However, there is a dearth of human studies on the identification of candidate phenotypes that serve as markers of cannabis dependence. The cannabinoid receptor type 1 (CB1), a G-coupled receptor encoded by the CNR1 gene, mediates the psychoactive effects and rewarding actions of marijuana (Ledent et al., 1999; Zhang et al., 2004). In addition, there is evidence that the fatty acid amidohydrolase (FAAH) gene may be an important candidate (Cravatt and Lichtman, 2003). Several polymorphisms in the CNR1 and one in the FAAH genes have been associated with cannabis dependence (Comings et al., 1997; Hopfer et al., 2006; Tyndale et al., 2007), cannabis-related intermediate phenotypes, including withdrawal and craving (Haughey et al, 2008), as well as positive subjective effects and physiological stimulation (Schacht et al., 2008). Despite previous suggestive findings, no studies have been conducted to date that test the association between CNR1 variability and key cannabis-related intermediate phenotypes related to sensitivity to the acute effects of cannabis, such as increased positive affect and reward sensitivity, decreased negative affect, and subjective stimulation and intoxication. Furthermore, it is largely unknown whether CNR1 or FAAH variation is associated with marijuana craving in non-abstinent users. The primary goal of this pilot research is to investigate variability in marijuana's acute and cue-elicited effects associated with empirically-chosen polymorphisms in the CNR1 and FAAH genes. In a 2 (genotype) X 2 (drug administration: marijuana with 2.8% delta-9-tetrahydrocannabinol (THC) vs. marijuana placebo; cue reactivity: neutral vs. marijuana cues) laboratory study, we will examine these effects in 80 Caucasian nontreatment- seeking heavy cannabis users. Genotyping of CNR1 and the FAAH genes will include empirically chosen candidate single nucleotide polymorphisms (SNPs) as well as tagSNPs. The long-term objective of this research is to identify genetic variation underlying individual differences in marijuana effects that may account for individual differences in susceptibility to marijuana dependence. Greater understanding of these mechanisms can inform genetically targeted pharmacotherapeutic approaches for treating cannabis dependence. PUBLIC HEALTH RELEVANCE: This research will help determine the reasons why some people who use marijuana may be at greater risk for abusing or becoming dependent on this drug. Examining individual differences in their genetic makeup will help uncover why some of these individuals may be more sensitive to marijuana's effects. This information could be of significant value to help identify people who would benefit from a particular treatment for marijuana.