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_2A receptor (5-HT_2AR) and 5-HT_2C receptor (5-HT_2CR), 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-HT_2AR antagonist/inverse agonist pimavanserin, selective 5-HT_2CR 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 on cocaine-seeking behavior. 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.

可卡因使用障碍 (CUD) 是一项重大的公共卫生挑战，目前尚无美国食品和药物管理局 (FDA) 批准的药物治疗药物。CUD 复发的倾向涉及几个脆弱性因素，包括对与吸食可卡因相关的线索的敏感性。5-羟色胺（5-羟色胺，5-HT）神经传递，特别是通过 5-HT _2A受体 (5-HT _2A R) 和 5-HT _2C受体 (5-HT _2C R)，在机械上与临床前研究中的可卡因寻求有关楷模。在本实验中，我们在雄性大鼠中采用自我给药试验来研究是否急性和/或重复给药 FDA 批准的选择性 5-HT _2AR 拮抗剂/反向激动剂匹马万色林、选择性 5-HT _2C R 激动剂氯卡色林或它们的组合会改变可卡因摄入和/或可卡因寻求行为。我们发现，氯卡色林的急性给药，而不是匹马万色林，减少了可卡因的摄入，而匹马万色林加氯卡色林不影响可卡因的自我给药。相比之下，10 天重复给予匹马万色林、氯卡色林或匹马万色林加氯卡色林在强制戒断可卡因自我给药期间，减弱可卡因寻求，类似于每种配体对可卡因寻求行为的急性给药。总之，这些数据揭示了用匹马万色林加氯卡色林重复治疗以减弱对 CUD 啮齿动物模型中的复发样行为重要的因素的功效。