COCAINE WITHDRAWAL: A WINDOW OF TREATMENT OPPORTUNITY

尽早戒除兴奋剂滥用可能是治疗的一个潜在窗口。相当多的证据表明，慢性间歇给药与连续给药会导致残留的戒断状态，即敏感型与耐受型。当在戒断后第7天进行测试时，一些改变的神经生物学机制与可卡因的致敏和耐受性有不同的关联。因此，不同的慢性给药制度允许不同的适应机制与致敏和耐受相分离。在文献中，敏感化和耐受性被假设为导致可卡因滥用者的几种情况，包括戒断后的麻木、渴求和强制用药行为以及复发。在某种程度上，在戒断过程中，敏感化与耐受性可以根据旧的反适应或对手过程假说来构想(Koob和Bloom，1988；Himmelsbach，1943)。对手过程可以是系统内的过程，也可以是系统变化之间的过程(Koob和Bloom，1988)。我们的研究发现，多巴胺机制在7-10天的戒断期内处于动态变化状态，这与相反过程假说的一种形式是一致的，该假说要求撤除期来建立或巩固适应机制。因此，这一早期停药期可能是改变残留效应巩固的治疗机会。由于与敏感性/耐受性相关的神经适应有助于高复发率，阐明其药理可逆性的手段将促进治疗可卡因成瘾者的药物开发努力。提出的假设、检验和筛选模型包括：1)给可卡因致敏和耐受14天；2)戒断前5天用候选治疗药物和对照治疗；3)在戒断第7天和以后测试敏化/耐受逆转和相关机制。我们目前对致敏/耐受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。

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.