COCAINE WITHDRAWAL: A WINDOW OF TREATMENT OPPORTUNITY

兴奋剂滥用的早期戒断可能是治疗的一个潜在窗口期。相当多的证据表明，慢性间歇性与连续可卡因给药方案诱导残留戒断状态，即致敏vs耐受性。当戒断后第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和耐受性不同。因此，不同的慢性给药方案允许敏化与耐受性的适应机制的明显分离。在文献中，敏化和耐受性被假设为可卡因滥用者的几种情况，包括戒断性神经痛、渴望和强迫性药物给药行为以及复发。在某种程度上，在戒断期间，敏化与耐受性可以根据旧的反适应或对抗过程假设来理解（Koob和Bloom, 1988; Himmelsbach, 1943）。对手过程可能是系统内部或系统变化之间的过程（Koob和Bloom， 1988）。我们的研究结果表明，多巴胺机制在7-10天的戒断期处于动态流变状态，这与对手过程假说的一种形式相一致，即戒断期需要适应性机制的建立或巩固。因此，这个早期停药期可能是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导致了高累犯率，阐明其药理学可逆性的手段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)给药14天的可卡因致敏和耐受性方案；2)停药前5天使用候选治疗药物和对照；3)在停药第7天及之后测试致敏/耐受性逆转及其相关机制。我们目前对致敏/耐受性相关机制的理解以及临床研究将指导和限制寻找治疗可卡因滥用的新药物。

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.