Center for Addiction Research and Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, Texas (D.J.S., S.J.S., R.G.F., N.C.A., K.A.C.); Department of Statistical Sciences and Operations Research, Institute for Drug and Alcohol Studies, Virginia Commonwealth University, Richmond, Virginia (E.L.B., Q.W.); Drug Design and Synthesis Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse, Bethesda, Maryland (K.C.R.); and Department of Psychiatry, Institute for Drug and Alcohol Studies, Virginia Commonwealth University, Richmond, Virginia (F.G.M.).
Center for Addiction Research and Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, Texas (D.J.S., S.J.S., R.G.F., N.C.A., K.A.C.); Department of Statistical Sciences and Operations Research, Institute for Drug and Alcohol Studies, Virginia Commonwealth University, Richmond, Virginia (E.L.B., Q.W.); Drug Design and Synthesis Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse, Bethesda, Maryland (K.C.R.); and Department of Psychiatry, Institute for Drug and Alcohol Studies, Virginia Commonwealth University, Richmond, Virginia (F.G.M.)
J Pharmacol Exp Ther. 2019 Jan;368(1):41-49. doi: 10.1124/jpet.118.251199. Epub 2018 Oct 29.
Impulsivity and the attentional orienting response to cocaine-associated cues () promote relapse in cocaine-use disorder (CUD). A time-dependent escalation of cue reactivity () occurs during extended, forced abstinence from cocaine self-administration in rats. The investigational serotonin (5-HT) 5-HT receptor (5-HTR) antagonist/inverse agonist M100907 suppresses , or the inability to withhold premature responses, and cocaine-seeking behaviors. The present preclinical study was designed to establish the potential for repurposing the Food and Drug Administration-approved selective 5-HTR antagonist/inverse agonist pimavanserin as a therapeutic agent to forestall relapse vulnerability in CUD. In male Sprague-Dawley rats, pimavanserin suppressed impulsive action () measured in the 1-choice serial reaction time (1-CSRT) task, similarly to M100907. We also used the 1-CSRT task to establish baseline levels of impulsive action before cocaine self-administration and evaluation of cue reactivity (lever presses reinforced by the discrete cue complex previously paired with cocaine delivery). We observed an incubation of cocaine cue reactivity between day 1 and day 30 of forced abstinence from cocaine self-administration. Baseline levels of impulsive action predicted incubated levels of cocaine cue reactivity in late abstinence. We also found that baseline impulsive action predicted the effectiveness of pimavanserin to suppress incubated cue reactivity in late abstinence from cocaine self-administration at doses that were ineffective in early abstinence. These data suggest that integration of clinical measures of impulsive action may inform refined, personalized pharmacotherapeutic intervention for the treatment of relapse vulnerability in CUD.
冲动和对可卡因相关线索的注意力定向反应()促进可卡因使用障碍(CUD)的复发。在大鼠中,从可卡因自我给药的延长、强制禁欲期间,线索反应()会出现时间依赖性的升级。研究中的血清素(5-HT)5-HT 受体(5-HTR)拮抗剂/反向激动剂 M100907 抑制(),或无法抑制过早反应,并抑制可卡因寻求行为。本临床前研究旨在确定将经美国食品和药物管理局批准的选择性 5-HTR 拮抗剂/反向激动剂 pimavanserin 重新用作治疗剂以预防 CUD 复发易感性的潜力。在雄性 Sprague-Dawley 大鼠中,pimavanserin 抑制了在 1 选择序列反应时间(1-CSRT)任务中测量的冲动行为(),与 M100907 相似。我们还使用 1-CSRT 任务在可卡因自我给药之前建立冲动行为的基线水平,并评估线索反应(由先前与可卡因给药配对的离散线索复合物强化的杠杆按压)。我们观察到在从可卡因自我给药的强制禁欲的第 1 天和第 30 天之间,可卡因线索反应的潜伏期。禁欲期间冲动行为的基线水平预测了潜伏期可卡因线索反应的水平。我们还发现,基线冲动行为预测了 pimavanserin 在从可卡因自我给药的晚期禁欲中抑制潜伏期线索反应的有效性,而在早期禁欲中,pimavanserin 的剂量无效。这些数据表明,冲动行为的临床测量的整合可能为 CUD 的复发易感性提供精细的、个性化的药物治疗干预。