Schacht Joseph P, Selling Rebecca E, Hutchison Kent E
University of Colorado at Boulder, Boulder, CO, USA.
Psychopharmacology (Berl). 2009 Apr;203(3):511-7. doi: 10.1007/s00213-008-1397-z. Epub 2008 Nov 12.
Cannabis dependence is a growing problem among individuals who use marijuana frequently, and genetic differences make some users more liable to progress to dependence. The identification of intermediate phenotypes of cannabis dependence may aid candidate genetic analysis. Promising intermediate phenotypes include craving for marijuana, withdrawal symptoms after abstinence, and sensitivity to its acute effects. A single nucleotide polymorphism (SNP) in the gene encoding for fatty acid amide hydrolase (FAAH) has demonstrated association with substance use disorder diagnoses, but has not been studied with respect to these narrower phenotypes. FAAH is an enzyme that inactivates anandamide, an endogenous agonist for CB(1) receptors (to which Delta(9)-tetrahydrocannabinol binds). CB(1) binding modulates mesocorticolimbic dopamine release, which underlies many facets of addiction.
The SNP, FAAH C385A (rs324420), was examined to determine whether its variance was associated with changes in craving and withdrawal after marijuana abstinence, craving after cue exposure, or sensitivity to the acute effects of marijuana.
Forty daily marijuana users abstained for 24 h, were presented with a cue-elicited craving paradigm and smoked a marijuana cigarette in the laboratory.
C385A variance was significantly associated with changes in withdrawal after abstinence, and happiness after smoking marijuana in the predicted directions, was associated with changes in heart rate after smoking in the opposite of the predicted direction, and was not associated with changes in craving or other acute effects.
These data lend support to some previous association studies of C385A, but suggest that further refinement of these intermediate phenotypes is necessary.
大麻依赖在频繁使用大麻的人群中是一个日益严重的问题，基因差异使一些使用者更容易发展为依赖。确定大麻依赖的中间表型可能有助于候选基因分析。有前景的中间表型包括对大麻的渴望、戒断后的戒断症状以及对其急性效应的敏感性。脂肪酸酰胺水解酶（FAAH）编码基因中的一个单核苷酸多态性（SNP）已显示与物质使用障碍诊断相关，但尚未针对这些更狭义的表型进行研究。FAAH是一种使花生四烯乙醇胺失活的酶，花生四烯乙醇胺是CB(1)受体的内源性激动剂（Δ9-四氢大麻酚与之结合）。CB(1)结合调节中脑边缘多巴胺释放，这是成瘾许多方面的基础。
研究SNP FAAH C385A（rs324420），以确定其变异是否与大麻戒断后的渴望和戒断变化、线索暴露后的渴望或对大麻急性效应的敏感性相关。
40名每日使用大麻的使用者戒断24小时，接受线索诱发的渴望范式，并在实验室吸食一支大麻烟。
C385A变异与戒断后的戒断变化显著相关，与吸食大麻后的幸福感呈预期方向相关，与吸食后的心率变化呈与预期相反的方向相关，与渴望或其他急性效应的变化无关。
这些数据支持了之前一些关于C385A的关联研究，但表明有必要对这些中间表型进行进一步细化。
