The CRFI Antagonist Verucerfont in Anxious Alcohol-Dependent Women: Translation of Neuroendocrine, But not of Anti-Craving Effects
The CRFI Antagonist Verucerfont in Anxious Alcohol-Dependent Women: Translation of Neuroendocrine, But not of Anti-Craving Effects
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DOI：
10.1038/npp.2016.61
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发表时间：
2016-11-01
影响因子：
7.6
通讯作者：
Heilig, Markus
中科院分区：
文献类型：
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作者：
Schwandt, Melanie L.;Cortes, Carlos R.;Heilig, Markus
阻断促肾上腺皮质激素释放因子受体I(CRFI)可抑制应激诱导的啮齿类动物的酒精寻求，但临床翻译仍存在。在这里，我们首先证明了cRFI拮抗剂verucerfont有效地阻断了肾上腺切除大鼠下丘脑-垂体肾上腺(HPA)轴的激活。然后，我们评估了verucerfont在阻断HPA轴激活和减少酒精依赖患者应激诱导的酒精渴求方面的能力。焦虑、酒精依赖的女性(年龄21-65岁，n=39)在NIH临床中心入院，如果需要，在入选前完成戒断治疗。在一周的单盲安慰剂之后，随机双盲使用马鞭草(每天350毫克)或安慰剂，为期3周。使用地塞米松-CRF测试评估了Verucerfont对HPA轴的影响-使用两种已建立的方案来评估渴求，一种是将社交应激源与身体酒精线索暴露相结合，另一种是使用引导图像来呈现个性化的压力、酒精或中性刺激。一次功能磁共振成像测试了大脑对负面情感刺激和酒精暗示的反应。与我们最近对另一种cRFI拮抗剂pquierfont的观察相反，verucerfont有效地阻断了HPA轴对地塞米松-CRF测试的反应，但没有影响酒精渴望。右侧杏仁核对负面情感刺激的反应显著减弱，但对酒精相关刺激的反应在某些大脑区域增加，包括左侧脑岛。在verucerfont组中，停药率显著更高。我们的发现提供了第一个翻译证据，即受体解离动力学较慢的cRFI拮抗剂可能具有更高的抑制HPA轴反应的疗效。这些发现并不支持阻断cRFI对应激诱导的酒精渴求和复发的临床疗效。
Blockade of corticotropin-releasing factor receptor I (CRFI) suppresses stress-induced alcohol seeking in rodents, but clinical translation remains. Here, we first showed that the CRFI antagonist verucerfont potently blocks hypothalamic-pituitary adrenal (HPA) axis activation in adrenalectomized rats. We then evaluated verucerfont for its ability to block HPA axis activation and reduce stress-induced alcohol craving in alcohol-dependent patients. Anxious, alcohol-dependent women (age 21-65 years, n = 39) were admitted to the NIH Clinical Center and completed withdrawal treatment before enrollment if needed. One-week single-blind placebo was followed by randomized double-blind verucerfont (350 mg per day) or placebo for 3 weeks. Verucerfont effects on the HPA axis were evaluated using the dexamethasone-CRF test Craving was evaluated using two established protocols, one that combines a social stressor with physical alcohol cue exposure, and one that uses guided imagery to present personalized stress, alcohol, or neutral stimuli. An fMRI session examined brain responses to negative affective stimuli and alcohol cues. In contrast to our recent observations with another CRFI antagonist, pexacerfont, verucerfont potently blocked the HPA axis response to the dexamethasone-CRF test, but left alcohol craving unaffected. Right amygdala responses to negative affective stimuli were significantly attenuated by verucerfont, but responses to alcohol-associated stimuli were increased in some brain regions, including left insula. Discontinuation rates were significantly higher in the verucerfont group. Our findings provide the first translational evidence that CRFI antagonists with slow receptor dissociation kinetics may have increased efficacy to dampen HPA axis responses. The findings do not support a clinical efficacy of CRFI blockade in stress-induced alcohol craving and relapse.