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

遗传变异与大麻的药理学和线索诱发效应

基本信息

批准号：
7928249
负责人：
Valerie S Knopik
金额：
$ 24.06万
依托单位：
BROWN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-15 至 2013-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7928249
关键词：
Accounting Acute Affect Amidohydrolases Behavioral Biochemical Biological Candidate Disease Gene Cannabinol Cannabis Caucasians Caucasoid Race Cues Fatty Acids Gene Targeting Genes Genetic Genetic Polymorphism Genetic Variation Genotype Goals Haplotypes Human Incentives Individual Individual Differences Intoxication Laboratory Study Link Literature Marijuana Marijuana Dependence Marijuana Smoking Measures Mediating Modeling Pharmaceutical Preparations Phenotype Physiological Placebos Positive Reinforcements Predisposition Process Research Rewards Risk Role Single Nucleotide Polymorphism Testing Tetrahydrocannabinol Variant Withdrawal addiction alcohol research base candidate identification cannabinoid receptor craving cue reactivity economic value gene environment interaction indexing pleasure public health relevance receptor receptor coupling reconstruction response

项目摘要

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.

描述（由申请人提供）：研究遗传变异影响大麻依赖和使用大麻倾向的机制是一个高度优先事项。然而，缺乏人类研究鉴定候选表型，作为大麻依赖的标志。大麻素受体1型（CB1）是一种由CNR1基因编码的g偶联受体，介导大麻的精神作用和奖励作用（Ledent et al., 1999; Zhang et al., 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基因的几个多态性和FAAH基因的一个多态性与大麻依赖有关（harms et al., 1997; Hopfer et al., 2006; Tyndale et al., 2007），大麻相关的中间表型，包括戒断和渴望（Haughey et al., 2008），以及积极的主观效应和生理刺激（Schacht et al., 2008）。尽管之前有一些提示性的发现，但迄今为止还没有研究测试CNR1变异性与大麻相关的关键中间表型之间的关系，这些表型与大麻对急性效应的敏感性有关，如积极影响和奖励敏感性增加，消极影响减少，主观刺激和中毒。此外，在非戒断使用者中，CNR1或FAAH变异是否与大麻渴望有关在很大程度上是未知的。本试点研究的主要目的是研究大麻的急性和线索诱导效应的可变性，这些可变性与CNR1和FAAH基因的经验选择多态性有关。在2（基因型）x2(给药：含有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)实验室研究，我们将在80名非寻求治疗的白人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选择的候选单核苷酸多态性（snp）以及标记snp。这项研究的长期目标是确定大麻影响的个体差异背后的遗传变异，这可能解释大麻依赖易感性的个体差异。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信息。