Synergism Between a Serotonin 5-HT2A Receptor (5-HT2AR) Antagonist and 5-HT2CR Agonist Suggests New Pharmacotherapeutics for Cocaine Addiction
Synergism Between a Serotonin 5-HT2A Receptor (5-HT2AR) Antagonist and 5-HT2CR Agonist Suggests New Pharmacotherapeutics for Cocaine Addiction
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DOI：
10.1021/cn300072u
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发表时间：
2013-01-01
影响因子：
5
通讯作者：
Moeller, F. Gerard
中科院分区：
文献类型：
--
作者：
Cunningham, Kathryn A.;Anastasio, Noelle C.;Moeller, F. Gerard
可卡因依赖的复发，即使是在长期禁欲之后，涉及许多责任因素，包括冲动性（对刺激做出快速、无计划反应的倾向，而不考虑负面后果）和线索反应性（对与可卡因服用相关的线索的敏感性，这可能会促进可卡因寻求）。这些因子通过5-HT 2A受体（5-HT 2AR）和5-HT 2CR与5-羟色胺（5-HT）信号传导机制相关;选择性5-HT 2AR拮抗剂或5-HT 2CR激动剂在临床前模型中抑制冲动和可卡因寻求。我们进行了概念验证分析，以评估5-HT 2AR拮抗剂加5-HT 2CR激动剂的组合是否对这些复发的易患因素具有协同作用，如在1选择系列反应时间任务和可卡因自我给药/恢复测定中所测量的。选择性5-HT 2AR拮抗剂M100907和5-HT 2CR激动剂WAY 163909联合给药（单独给药无效）可协同抑制可卡因诱导的活动过度、固有和可卡因诱发的冲动行为以及可卡因寻求行为的线索和可卡因引发的恢复。鉴定5-HT 2AR拮抗剂加5-HT 2CR激动剂之间的协同作用以减弱这些在复发中重要的因素，表明双功能配体作为抗成瘾药物的前景，为开发具有改善的功效、效力、选择性和个体分子的体内特征的新配体奠定了基础。
Relapse to cocaine dependence, even after extended abstinence, involves a number of liability factors including impulsivity (predisposition toward rapid, unplanned reactions to stimuli without regard to negative consequences) and cue reactivity (sensitivity to cues associated with cocaine-taking which can promote cocaine-seeking). These factors have been mechanistically linked to serotonin (5-hydroxytryptamine, 5-HT) signaling through the 5-HT2A receptor (5-HT2AR) and 5-HT2CR; either a selective 5-HT2AR antagonist or a 5-HT2CR agonist suppresses impulsivity and cocaine-seeking in preclinical models. We conducted proof-of-concept analyses to evaluate whether a combination of 5-HT2AR antagonist plus 5-HT2CR agonist would have synergistic effects over these liability factors for relapse as measured in a 1-choice serial reaction time task and cocaine self-administration/reinstatement assay. Combined administration of a dose of the selective 5-HT2AR antagonist M100907 plus the 5-HT2CR agonist WAY163909, each ineffective alone, synergistically suppressed cocaine-induced hyperactivity, inherent and cocaine-evoked impulsive action, as well as cue- and cocaine-primed reinstatement of cocaine-seeking behavior. The identification of synergism between a 5-HT2AR antagonist plus a 5-HT2CR agonist to attenuate these factors important in relapse indicates the promise of a bifunctional ligand as an anti-addiction pharmacotherapeutic, setting the stage to develop new ligands with improved efficacy, potency, selectivity, and in vivo profiles over the individual molecules.