Ma Yihe, Giardino William J
Department of Psychiatry & Behavioral Sciences and Wu Tsai Neurosciences Institute, Stanford University School of Medicine, Stanford, CA, USA.
Addict Neurosci. 2022 Sep;3. doi: 10.1016/j.addicn.2022.100024. Epub 2022 Jun 17.
Given historical focus on the roles for cholecystokinin (CCK) as a peripheral hormone controlling gastrointestinal processes and a brainstem peptide regulating food intake, the study of CCK as a limbic neuromodulator coordinating reward-seeking and emotional behavior remains underappreciated. Furthermore, localization of CCK to specialized interneurons throughout the hippocampus and cortex relegated CCK to being examined primarily as a static cell type marker rather than a dynamic functional neuromodulator. Yet, over three decades of literature have been generated by efforts to delineate the central mechanisms of addiction-related behaviors mediated by the CCK system across the striatum, amygdala, hypothalamus, and midbrain. Here, we cover fundamental findings that implicate CCK neuron activity and CCK receptor signaling in modulating drug intake and drug-seeking (focusing on psychostimulants, opioids, and alcohol). In doing so, we highlight the few studies that indicate sex differences in CCK expression and corresponding drug effects, emphasizing the importance of examining hormonal influences and sex as a biological variable in translating basic science discoveries to effective treatments for substance use disorders in human patients. Finally, we point toward understudied subcortical sources of endogenous CCK and describe how continued neurotechnology advancements can be leveraged to modernize understanding of the neural circuit mechanisms underlying CCK release and signaling in addiction-relevant behaviors.
鉴于历史上对胆囊收缩素（CCK）作为控制胃肠道过程的外周激素以及调节食物摄入的脑干肽的作用的关注，对CCK作为协调寻求奖励和情绪行为的边缘神经调节剂的研究仍未得到充分重视。此外，CCK在整个海马体和皮质的特殊中间神经元中的定位使CCK主要被视为一种静态细胞类型标记物，而非动态功能性神经调节剂。然而，三十多年来，人们一直致力于描绘由CCK系统介导的纹状体、杏仁核、下丘脑和中脑的成瘾相关行为的中枢机制，产生了大量文献。在此，我们涵盖了一些基本发现，这些发现表明CCK神经元活动和CCK受体信号传导在调节药物摄入和药物寻求行为（重点关注精神兴奋剂、阿片类药物和酒精）中发挥作用。在此过程中，我们强调了少数表明CCK表达存在性别差异以及相应药物效应的研究，强调了在将基础科学发现转化为人类患者物质使用障碍的有效治疗方法时，研究激素影响和性别作为生物学变量的重要性。最后，我们指出了对内源性CCK的皮质下来源研究不足的问题，并描述了如何利用持续的神经技术进步来更新对成瘾相关行为中CCK释放和信号传导的神经回路机制的理解。
