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

描述（由申请人提供）：遗传变异性影响大麻依赖性和使用大麻倾向的机制的检查是一个高度优先事项。然而，在确定作为大麻依赖标志物的候选表型方面缺乏人类研究。大麻素受体1型（CB 1），一种由CNR 1基因编码的G偶联受体，介导大麻的精神活性作用和奖励作用（Ledent等人，1999; Zhang等人，2004年）。此外，有证据表明脂肪酸酰胺水解酶（FAAH）基因可能是一个重要的候选基因（Cravatt和Lichtman，2003）。CNR 1中的几种多态性和FAAH基因中的一种多态性与大麻依赖性有关（Comings等人，1997; Hopfer等人，2006; Tyndale等人，2007），大麻相关的中间表型，包括戒断和渴望（Haughey等人，2008），以及积极的主观效应和生理刺激（Schacht等人，2008年）。尽管以前的提示性发现，迄今为止还没有进行任何研究来测试CNR 1变异性和与大麻急性效应敏感性相关的关键大麻相关中间表型之间的关联，例如增加积极影响和奖励敏感性，减少消极影响，以及主观刺激和中毒。此外，CNR 1或FAAH变异是否与非禁欲用户的大麻渴望有关在很大程度上是未知的。这项试点研究的主要目标是调查大麻的急性和线索引起的影响与CNR 1和FAAH基因中的随机选择的多态性相关的变异性。在一项2（基因型）× 2（药物给药：含2.8% δ-9-四氢大麻酚（THC）的大麻与大麻安慰剂;线索反应性：中性与大麻线索）的实验室研究中，我们将在80名白人非寻求治疗的重度大麻使用者中检查这些影响. CNR 1和FAAH基因的基因分型将包括凭经验选择的候选单核苷酸多态性（SNP）以及tagSNP。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，这可能是大麻依赖易感性个体差异的原因。更好地了解这些机制可以为治疗大麻依赖的遗传靶向药物治疗方法提供信息。 公共卫生相关性：这项研究将有助于确定为什么一些使用大麻的人可能有更大的滥用或依赖这种药物的风险。检查他们基因组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。这些信息可能具有重要价值，有助于确定谁将受益于大麻的特定治疗。

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.