Department of Psychiatry, Columbia University Irving Medical Center and the New York State Psychiatric Institute, New York, NY, USA.
Yale PET Center, Department of Radiology and Biomedical Imaging, Yale University School of Medicine, New Haven, CT, USA.
Neuropsychopharmacology. 2019 Sep;44(10):1720-1727. doi: 10.1038/s41386-019-0398-4. Epub 2019 Apr 26.
Animal studies indicate that the kappa-opioid receptor/dynorphin system plays an important role in cocaine binges and stress-induced relapse. Our goal was to investigate changes in kappa-opioid receptor (KOR) availability in the human brain using positron emission tomography (PET), before and after a cocaine binge. We also investigated the correlation between KOR and stress-induced cocaine self-administration. PET imaging was performed with the KOR selective agonist [C]GR103545. Subjects with cocaine-use disorder (CUD) underwent PET scans and performed two types of cocaine self-administration sessions in the laboratory as follows: (1) choice sessions following a cold pressor test, to induce stress, and (2) binge dosing of cocaine. This allowed us investigate the following: (1) the association between KOR binding and a laboratory model of stress-induced relapse and (2) the change in KOR binding following a 3-day cocaine binge, which is thought to represent a change in endogenous dynorphin. A group of matched healthy controls was included to investigate between group differences in KOR availability. A significant association between [C]GR103545 binding and cocaine self-administration was seen: greater KOR availability was associated with more choices for cocaine. In addition, the 3-day cocaine binge significantly reduced [C]GR103545 binding by 18% in the striatum and 14% across brain regions. No difference in [C]GR103545 binding was found between the CUD subjects and matched controls. In the context of previous studies, these findings add to the growing evidence that pharmacotherapies targeting the KOR have the potential to significantly impact treatment development for cocaine-use disorder.
动物研究表明，κ-阿片受体/强啡肽系统在可卡因狂欢和应激诱导的复吸中发挥着重要作用。我们的目标是使用正电子发射断层扫描（PET），在可卡因狂欢前后，研究人类大脑中κ-阿片受体（KOR）的可用性变化。我们还研究了 KOR 与应激诱导的可卡因自我给药之间的相关性。使用 KOR 选择性激动剂 [C]GR103545 进行 PET 成像。可卡因使用障碍（CUD）患者接受 PET 扫描，并在实验室中进行两种类型的可卡因自我给药：（1）冷加压试验后进行选择，以诱导应激，（2）可卡因狂欢剂量。这使我们能够研究以下内容：（1）KOR 结合与应激诱导复吸的实验室模型之间的关联，以及（2）在为期 3 天的可卡因狂欢后 KOR 结合的变化，这被认为是内源性强啡肽的变化。纳入一组匹配的健康对照者，以研究 KOR 可用性的组间差异。[C]GR103545 结合与可卡因自我给药之间存在显著相关性：更高的 KOR 可用性与更多可卡因的选择有关。此外，为期 3 天的可卡因狂欢显著降低了纹状体中的 [C]GR103545 结合 18%，整个大脑区域降低了 14%。在 CUD 患者和匹配的对照组之间，未发现 [C]GR103545 结合的差异。在之前研究的背景下，这些发现增加了越来越多的证据，表明靶向 KOR 的药物治疗有潜力对可卡因使用障碍的治疗发展产生重大影响。
