Kutvolgyi Clinical Centre, Semmelweis University, Budapest, Hungary.
Trends Pharmacol Sci. 2011 May;32(5):270-80. doi: 10.1016/j.tips.2011.02.013. Epub 2011 Apr 16.
Antagonists of cannabinoid type-1 (CB₁) receptors have been explored as therapeutic agents for obesity and addiction. However, use of rimonabant (the first marketed CB₁ receptor antagonist) has been suspended due to its anxiogenic and depressive side effects (including suicide risk). Recent genomic studies provide evidence that variants of the CB₁ receptor gene (CNR1) alone or in combination with the gene of the serotonin transporter (SLC6A4) contribute to the development of anxiety and/or depression, suggesting that high-risk individuals could be identified through genetic testing. In this review, we argue that identification of high-risk individuals by a combination of genomic screening, previous risk phenotype, and environmental risk factors offers a promising method for the safe use of centrally acting CB₁ receptor antagonists. We summarize endocannabinoid signaling in pathways related to anxiety and depression, identify the serotonergic system as the most likely candidate to mediate the side effects of CB₁ receptor antagonists, and propose that poloymorphisms in CNR1, SLC6A4 and certain CYP 450 enzymes could help to identify individuals who may benefit from treatment with CB₁ receptor antagonist without psychiatric side effects.
大麻素类型 1 (CB₁) 受体拮抗剂已被探索用于治疗肥胖症和成瘾。然而，由于其焦虑和抑郁副作用（包括自杀风险），利莫那班（第一个上市的 CB₁ 受体拮抗剂）的使用已被暂停。最近的基因组研究提供了证据，表明 CB₁ 受体基因 (CNR1) 的变体单独或与 5-羟色胺转运体 (SLC6A4) 的基因结合，有助于焦虑和/或抑郁的发展，这表明可以通过基因测试识别高风险个体。在这篇综述中，我们认为通过基因组筛查、先前的风险表型和环境风险因素的组合来识别高风险个体，为安全使用中枢作用 CB₁ 受体拮抗剂提供了一种很有前途的方法。我们总结了与焦虑和抑郁相关的内源性大麻素信号通路，确定 5-羟色胺能系统最有可能介导 CB₁ 受体拮抗剂的副作用，并提出 CNR1、SLC6A4 和某些 CYP 450 酶的多态性可能有助于识别可能受益于 CB₁ 受体拮抗剂治疗而无精神副作用的个体。
