Institute for Drug and Alcohol Studies, Virginia Commonwealth University, Richmond, VA, United States.
Department of Psychiatry, Virginia Commonwealth University, Richmond, VA, United States.
Transl Psychiatry. 2022 May 6;12(1):187. doi: 10.1038/s41398-022-01934-w.
Cocaine use disorder (CUD) patients display heterogenous symptoms and unforeseeable responses to available treatment approaches, highlighting the need to identify objective, accessible biobehavioral signatures to predict clinical trial success in this population. In the present experiments, we employed a task-based behavioral and pharmacogenetic-fMRI approach to address this gap. Craving, an intense desire to take cocaine, can be evoked by exposure to cocaine-associated stimuli which can trigger relapse during attempted recovery. Attentional bias towards cocaine-associated words is linked to enhanced effective connectivity (EC) from the anterior cingulate cortex (ACC) to hippocampus in CUD participants, an observation which was replicated in a new cohort of participants in the present studies. Serotonin regulates attentional bias to cocaine and the serotonergic antagonist mirtazapine decreased activated EC associated with attentional bias, with greater effectiveness in those CUD participants carrying the wild-type 5-HTR gene relative to a 5-HTR single nucleotide polymorphism (rs6318). These data suggest that the wild-type 5-HTR is necessary for the efficacy of mirtazapine to decrease activated EC in CUD participants and that mirtazapine may serve as an abstinence enhancer to mitigate brain substrates of craving in response to cocaine-associated stimuli in participants with this pharmacogenetic descriptor. These results are distinctive in outlining a richer "fingerprint" of the complex neurocircuitry, behavior and pharmacogenetics profile of CUD participants which may provide insight into success of future medications development projects.
可卡因使用障碍（CUD）患者表现出不同的症状和不可预测的治疗反应，这突出表明需要确定客观、可及的生物行为特征，以预测该人群临床试验的成功。在本实验中，我们采用了基于任务的行为和遗传药理学 fMRI 方法来解决这一差距。渴望，即强烈地想要服用可卡因，可以通过暴露于可卡因相关的刺激来引发，这些刺激在试图康复期间可能会引发复发。CUD 参与者对可卡因相关单词的注意力偏向与 ACC 到海马体的有效连通性（EC）增强有关，这一观察结果在本研究的新参与者队列中得到了复制。血清素调节对可卡因的注意力偏向，而 5-羟色胺拮抗剂米氮平降低了与注意力偏向相关的激活 EC，在携带野生型 5-HTR 基因的 CUD 参与者中效果更大，而在 5-HTR 单核苷酸多态性（rs6318）中效果较小。这些数据表明，野生型 5-HTR 是米氮平降低 CUD 参与者激活 EC 有效性所必需的，米氮平可能作为一种戒断增强剂，以减轻具有这种遗传药理学特征的参与者对可卡因相关刺激的渴望的大脑基质。这些结果的独特之处在于概述了 CUD 参与者复杂的神经回路、行为和遗传药理学特征的更丰富的“指纹”，这可能为未来药物开发项目的成功提供了一些见解。
