Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC 27710, United States.
Drug Alcohol Depend. 2012 Jul 1;124(1-2):11-8. doi: 10.1016/j.drugalcdep.2012.01.021. Epub 2012 Feb 21.
Psychostimulant abuse continues to present legal, socioeconomic and medical challenges as a primary psychiatric disorder, and represents a significant comorbid factor in major psychiatric and medical illnesses. To date, monotherapeutic drug treatments have not proven effective in promoting long-term abstinence in psychostimulant abusers. In contrast to clinical trials utilizing monotherapies, combinations of dopamine (DA) agonists and selective 5-HT(3), 5HT(2A/2C), or NK(1) antagonists have shown robust efficacy in reversing behavioral and neurobiological alterations in animal models of psychostimulant abuse. One important temporal requirement for these treatments is that the 5-HT or NK(1) receptor antagonist be given at a critical time window after DA agonist administration. This requirement may reflect a necessary dosing regimen towards normalizing underlying dysfunctional neural circuits and "addiction memory" states. Indeed, chronic psychostimulant abuse can be conceptualized as a consolidated form of dysfunctional memory maintained by repeated drug- or cue-induced reactivation of neural circuit and subsequent reconsolidation. According to this concept, the DA agonist given first may reactivate this memory circuit, thereby rendering it transiently labile. The subsequent antagonist is hypothesized to disrupt reconsolidation necessary for restabilization, thus leading progressively to a therapeutically-mediated abolishment of dysfunctional synaptic plasticity. We propose that long-term abstinence in psychostimulant abusers may be achieved not only by targeting putative mechanistic pathways, but also by optimizing drug treatment regimens designed to disrupt the neural processes underlying the addicted state.
药物滥用继续呈现法律、社会经济和医学方面的挑战，是一种主要的精神障碍，也是重大精神和医学疾病的重要合并因素。迄今为止，单一药物治疗并未证明在促进药物滥用者长期戒除方面有效。与利用单一疗法的临床试验相反，多巴胺 (DA) 激动剂与选择性 5-HT(3)、5HT(2A/2C) 或 NK(1)拮抗剂的联合治疗在逆转药物滥用动物模型中的行为和神经生物学改变方面显示出强大的疗效。这些治疗的一个重要时间要求是，在给予 DA 激动剂后，必须在关键的时间窗口内给予 5-HT 或 NK(1)受体拮抗剂。这一要求可能反映了一种必要的给药方案，以纠正潜在的功能失调神经回路和“成瘾记忆”状态。事实上，慢性药物滥用可以被概念化为一种由反复药物或线索诱导的神经回路重新激活和随后的再巩固所维持的功能失调记忆的巩固形式。根据这一概念，首先给予的 DA 激动剂可能会重新激活该记忆回路，从而使其暂时不稳定。随后的拮抗剂被假设会破坏重新巩固所必需的稳定，从而导致功能失调的突触可塑性逐渐被治疗介导消除。我们提出，药物滥用者的长期戒除不仅可以通过针对潜在的机制途径来实现，还可以通过优化药物治疗方案来破坏成瘾状态下的神经过程。
