Center for Addiction Research and Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX, USA; C. Kenneth and Dianne Wright Center for Clinical and Translational Research, Departments of Psychiatry and Pharmacology and Toxicology, Virginia Commonwealth University School of Medicine, Richmond, VA, USA.
C. Kenneth and Dianne Wright Center for Clinical and Translational Research, Departments of Psychiatry and Pharmacology and Toxicology, Virginia Commonwealth University School of Medicine, Richmond, VA, USA.
Neuropharmacology. 2020 May 15;168:108009. doi: 10.1016/j.neuropharm.2020.108009. Epub 2020 Feb 14.
Cocaine use disorder (CUD) is a major public health challenge for which there are no pharmacotherapeutics approved by the United States Food and Drug Administration (FDA). The propensity to relapse in CUD involves several vulnerability factors including sensitivity to cues associated with cocaine-taking. Serotonin (5-hydroxytryptamine, 5-HT) neurotransmission, particularly through the 5-HT receptor (5-HTR) and 5-HT receptor (5-HTR), is mechanistically linked to cocaine-seeking in preclinical models. In the present experiments, we employed self-administration assays in male rats to investigate whether acute and/or repeated administration of the FDA-approved selective 5-HTR antagonist/inverse agonist pimavanserin, selective 5-HTR agonist lorcaserin or their combination would alter cocaine intake and/or cocaine-seeking behavior. We found that acute administration of lorcaserin, but not pimavanserin, attenuated cocaine intake while pimavanserin plus lorcaserin did not impact cocaine self-administration. In contrast, 10-days of repeated administration of pimavanserin, lorcaserin, or pimavanserin plus lorcaserin during forced abstinence from cocaine self-administration, blunted cocaine-seeking, similar to the acute administration of each ligand. Taken together, these data reveal the efficacy of repeated treatment with pimavanserin plus lorcaserin to attenuate factors important to relapse-like behaviors in rodent models of CUD. This article is part of the special issue entitled 'Serotonin Research: Crossing Scales and Boundaries'.
可卡因使用障碍（CUD）是一个重大的公共健康挑战，目前美国食品和药物管理局（FDA）尚未批准任何药物治疗。CUD 的复发倾向涉及多个易感性因素，包括对与可卡因使用相关的线索的敏感性。在临床前模型中，血清素（5-羟色胺，5-HT）神经传递，特别是通过 5-HT 受体（5-HTR）和 5-HT 受体（5-HTR），与可卡因寻求有关。在本实验中，我们使用雄性大鼠的自我给药测定来研究 FDA 批准的选择性 5-HTR 拮抗剂/反向激动剂 pimavanserin、选择性 5-HT 激动剂 lorcaserin 或它们的组合是否会改变可卡因的摄入量和/或可卡因寻求行为。我们发现，急性给予 lorcaserin 而非 pimavanserin 可减轻可卡因的摄入量，而 pimavanserin 加 lorcaserin 则不会影响可卡因的自我给药。相比之下，在可卡因自我给药的强制戒断期间重复给予 10 天的 pimavanserin、lorcaserin 或 pimavanserin 加 lorcaserin，会削弱可卡因的寻求行为，类似于每种配体的急性给药。总之，这些数据揭示了重复给予 pimavanserin 加 lorcaserin 治疗可减轻 CUD 啮齿动物模型中与复发样行为相关的重要因素的疗效。本文是主题为“血清素研究：跨越尺度和边界”的特刊的一部分。
