COCAINE WITHDRAWAL: A WINDOW OF TREATMENT OPPORTUNITY

早期戒断兴奋剂滥用可能是一个潜在的治疗窗口。 相当多的证据表明，慢性间歇与连续可卡因给药方案诱导残留戒断状态，即，敏感性与耐受性。当在戒断后第7天进行测试时，许多改变的神经生物学机制与可卡因给药的致敏性和耐受性不同。 因此，不同的长期给药方案允许明显分离致敏与耐受的适应机制。 在文献中，敏感性和耐受性被假设为导致可卡因滥用者的几种情况，包括戒断性无力、渴望和强迫性给药行为以及复发。 在某种程度上，在退缩过程中，敏感与耐受可以根据旧的反适应或对手过程假设来设想（Koob和Bloom，1988; Himmelsbach，1943）。对手进程可能是系统内或系统之间的变化（Koob和Bloom，1988）。 我们的研究结果表明，多巴胺机制在7 - 10天的停药期处于动态流动状态，这与对手过程假说的一种形式相一致，该假说要求停药期用于建立或巩固适应机制。 因此，该提前停药期可能代表了改变残留效应巩固的治疗机会。 在某种程度上，与致敏/耐受性相关的神经适应性导致高再犯率，阐明其药理学可逆性的方法将促进治疗可卡因成瘾者的药物开发工作。 提出的假设、检验和筛选模型包括：1）给予可卡因致敏和耐受方案14天; 2）在停药前5天给予候选治疗药物和对照; 3）在停药第7天及以后检验致敏/耐受和相关机制的逆转。 我们目前对与致敏/耐受相关的机制的理解以及临床研究将指导和限制对可卡因滥用的新药物的寻找。

Early withdrawal from stimulant abuse may represent a potential window for treatment. Considerable evidence demonstrates that chronic intermittent vs. continuous cocaine dosing regimes induce residual withdrawal states, i.e., sensitization vs. tolerance. When tested on day 7 after withdrawal, a number of altered neurobiological mechanisms are differently associated with sensitization vs. tolerance to cocaine administration. Thus, the different chronic dosing regimes allow distinct separation of adapted mechanisms underlying sensitization vs. tolerance. In the literature, sensitization and tolerance have been hypothesized to contribute several conditions in cocaine abusers including withdrawal anergia, craving and compulsive drug administration behaviors as well as relapse. To some extent, during withdrawal, sensitization versus tolerance can be conceived of in terms of the old counter-adaptation or opponent process hypothesis (Koob and Bloom, 1988; Himmelsbach, 1943). The opponent process may be a within system or between system changes (Koob and Bloom, 1988). Our findings that dopamine mechanisms are in a state of dynamic flux in the 7-10 day withdrawal period is consistent with a form of the opponent process hypothesis which requires the withdrawal period for the establishment or consolidation of adaptive mechanisms. Thus, this early withdrawal period may represent a treatment opportunity to alter the consolidation of residual effects. To the extent the neuroadaptations related to sensitization/tolerance contribute to high rate of recidivism, an elucidation of means for their pharmacological reversibility will advance medication development efforts for treating cocaine addicts. The proposed hypothesis, testing, and screening model includes: 1) dosing with cocaine sensitization and tolerance regimes for 14 days; 2) treating with the candidate therapeutic drug and controls for the first 5 days of withdrawal; and 3) testing on withdrawal day 7 and laterfor reversal of sensitization/tolerance and associated mechanisms. Our current understanding of the mechanisms associated with sensitization/tolerance as well as clinical studies will guide and constrain the search for new medications for cocaine abuse.