Cocaine Withdrawal: A Window of Treatment Opportunity

描述（由申请人提供）：我们的可卡因滥用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。我们以前已经证明，这些时期的特点是机械流，在此期间，不仅可卡因敏化/巩固发生，而且以前建立的敏化和/或渐进比例可卡因自我管理可以逆转与5-HT 3或5-HT 2A拮抗剂。这些拮抗剂的动物数据与临床数据一致，证明了多氮平（一种混合的5-HT 3和5-HT 2拮抗剂）可显著降低精神分裂症患者和药物滥用者的兴奋剂滥用。本建议强调使用非滥用药物（例如，马吲哚或培高利特）以模拟每日急性可卡因戒断，随后用5-HT 3、5-HT 2A或NMDA拮抗剂靶向。马吲哚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-HT 2A受体具有高激动剂亲和力。我们提出的治疗策略不仅是扭转先前建立的可卡因致敏，但也保持脱敏状态，从而促进可卡因戒断。我们将通过运动测量和行为评级快速筛选推定的治疗方案;随后将检查表现出显著疗效的逆转行为致敏的治疗，以逆转渐进比例自我给药和神经生物学致敏标志物。我们的神经生物学标志物包括那些已经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志物（例如，NR 2B/GluR 1亚基表达，多巴胺/谷氨酸外流）。在某种程度上，敏感性参与可卡因滥用者的累犯，我们的药物开发计划提供了一个路线图的治疗干预，不仅是基于特定的药物，但也许更重要的是，对治疗剂量方案。我们假设，当人类滥用者每天使用时，在随后的急性戒断期内使用非滥用兴奋剂和拮抗剂的组合可能会促进脱敏状态或禁欲的长期维持。

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.