Ma Liangsuo, Steinberg Joel L, Bjork James M, Woisard Kyle, Zuniga Edward, Cunningham Kathryn A, Moeller F Gerard
Institute for Drug and Alcohol Studies, Virginia Commonwealth University, Richmond, VA, USA; Department of Psychiatry, Virginia Commonwealth University, Richmond, VA, USA.
Institute for Drug and Alcohol Studies, Virginia Commonwealth University, Richmond, VA, USA; Department of Psychiatry, Virginia Commonwealth University, Richmond, VA, USA.
Psychiatry Res Neuroimaging. 2025 Jul 23;352:112034. doi: 10.1016/j.pscychresns.2025.112034.
Understanding the neural mechanisms of drug cue reactivity may improve understanding of therapeutic targets for substance use disorders (SUDs). Preclinical studies indicate that the serotonin (5-HT) 5-HT receptor (5-HTR) and 5-HTR systems considerably but oppositely impact relapse vulnerability. Specifically, 5-HTR antagonists and 5-HTR agonists reduce drug-seeking behavior and reactivity to drug cues. Our previous neuroimaging study showed that mirtazapine (a non-selective 5-HTR antagonist) can reduce the effective connectivity (EC) of the pathway from the anterior cingulate cortex (ACC) to the hippocampus. The EC of this pathway has been consistently found to be associated with attentional bias towards drug cues in individuals with SUDs. To extend this finding, we investigated the effect of lorcaserin (a 5-HTR agonist) on the EC linked to attentional bias elicited by drug-related cues by employing dynamic causal modeling on functional magnetic resonance imaging data acquired during a drug-word Stroop task performed by 45 individuals diagnosed with SUDs. We observed a marginally positive correlation between the ACC → hippocampus EC and drug cue-related attentional bias at the pretreatment baseline. Furthermore, compared to the placebo condition, 7-day administration of lorcaserin reduced the ACC → hippocampus EC. Notably, these EC outcomes remained unaffected by factors such as handedness, presence of drug metabolites in urine, pretreatment urine drug screen, and the type of substance used. This study contributes further evidence of serotonergic regulation of the ACC → hippocampus EC, and the potential for this EC to be an early signal of target engagement for medication to treat SUDs.
了解药物线索反应性的神经机制可能有助于增进对物质使用障碍（SUDs）治疗靶点的理解。临床前研究表明，血清素（5-HT）5-HT受体（5-HTR）和5-HTR系统对复发易感性有显著但相反的影响。具体而言，5-HTR拮抗剂和5-HTR激动剂可减少觅药行为和对药物线索的反应性。我们之前的神经影像学研究表明，米氮平（一种非选择性5-HTR拮抗剂）可降低从前扣带回皮质（ACC）到海马体的通路的有效连接性（EC）。一直以来都发现该通路的EC与SUDs患者对药物线索的注意偏向有关。为了扩展这一发现，我们通过对45名被诊断为SUDs的个体在执行药物-文字Stroop任务期间获取的功能磁共振成像数据进行动态因果模型分析，研究了洛卡塞林（一种5-HTR激动剂）对与药物相关线索引发的注意偏向相关的EC的影响。我们在治疗前基线时观察到ACC→海马体EC与药物线索相关的注意偏向之间存在微弱的正相关。此外，与安慰剂组相比，洛卡塞林7天给药可降低ACC→海马体EC。值得注意的是，这些EC结果不受诸如利手、尿液中药物代谢物的存在、治疗前尿液药物筛查以及使用的物质类型等因素的影响。本研究进一步证明了血清素能对ACC→海马体EC的调节作用，以及该EC作为治疗SUDs药物靶点参与的早期信号的潜力。
