Cocaine Withdrawal: A Window of Treatment Opportunity

描述（由申请人提供）：我们针对可卡因滥用的药物开发计划是基于使用急性和慢性戒断期作为治疗机会的窗口。我们之前已经证明，这些时期具有机械通量的特征，在此期间，不仅会发生可卡因致敏/巩固，而且之前建立的致敏和/或渐进比例可卡因自我给药也可以通过5-HT3或5-HT2A拮抗剂逆转。这些拮抗剂的动物数据与临床数据一致，表明dodoapine是一种5-HT3和5-HT2混合拮抗剂，可显著减少精神分裂症患者和药物滥用者的兴奋剂滥用。目前的建议强调使用非滥用药物（例如，mazindol或培高利特）来模拟每日急性可卡因戒断，随后以5-HT3, 5-HT2A或NMDA拮抗剂为目标。Mazindol通过摄取抑制增加多巴胺和5-HT神经传递，而培高利特对D2和5-HT2A受体具有高的激动剂亲和力。我们提出的治疗策略不仅是扭转先前建立的可卡因致敏，而且要保持去敏状态，从而促进可卡因戒断。我们将通过运动测量和行为评分快速筛选可能的治疗方案；表现出显著疗效逆转行为致敏的治疗将随后检查进展比自我给药和神经生物学致敏标记的逆转。我们的神经生物学标记包括那些被反复证明与慢性可卡因注射和随后的戒断后致敏建立相关的标记（例如，NR2B / GluR1亚基表达，多巴胺/谷氨酸外排）。在某种程度上，致敏性与可卡因滥用者的再犯有关，我们的药物开发项目为治疗干预提供了一个路线图，它不仅基于特定的药物，也许更重要的是，基于治疗剂量方案。我们假设，当人类滥用者每天使用时，在随后的急性戒断期间给予非滥用兴奋剂和拮抗剂的组合可能促进长期维持脱敏状态或戒断。

DESCRIPTION (provided by applicant): Our medication development program for cocaine abuse is based on using the acute and chronic withdrawal periods as windows of treatment opportunity. We have previously demonstrated that these periods are characterized by mechanistic flux, during which, not only cocaine ensitization/consolidation take place, but also previously established sensitization and/or progressive ratio cocaine self administration can be reversed with 5-HT3 or 5-HT2A antagonists. The animal data with these antagonists are consistent with clinical data demonstrating that dozapine, a mixed 5-HT3 and 5-HT2 antagonist, substantially reduces stimulant abuse in both schizophrenics and drug abusers. The present proposal emphasizes the use of a non-abused drug (e.g., mazindol or pergolide) to simulate daily acute cocaine withdrawal, which is subsequently targeted with a 5-HT3, 5-HT2A or NMDA antagonists. Mazindol increases both dopamine and 5-HT neurotransmission by uptake inhibition, while pergolide has high agonist affinity at both D2 and 5-HT2A receptors. Our proposed treatment strategy is not only to reverse previously established cocaine sensitization but also to maintain the de-sensitized state and thus facilitate cocaine abstinence. We will rapidly screen putative treatment regimens with locomotor measurement and behavior rating; treatments exhibiting significant efficacy reversing behavioral sensitization will be subsequently examined for reversal of progressive ratio self-administration and neurobiological sensitization markers. Our neurobiological markers include the ones that have been repeatedly demonstrated to be associated with sensitization establishment following chronic cocaine injections and subsequent withdrawal (e.g., NR2B / GluR1 subunit expression, dopamine/glutamate efflux). To the extent that sensitization is involved in recidivism in cocaine abusers, our medication development program provides a road map for treatment intervention that is based not only on specific drugs, but perhaps more importantly, on the treatment dosing regimen. We hypothesize that, when used on a daily basis by human abusers, a combination of non-abused stimulant and an antagonist administered during the ensuing acute withdrawal period may promote long-term maintenance of a desensitized state or abstinence.