Rothman Richard B, Blough Bruce E, Baumann Michael H
Clinical Psychopharmacology Section, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, Baltimore, MD 21224, USA.
AAPS J. 2007 Jan 5;9(1):E1-10. doi: 10.1208/aapsj0901001.
We have advocated the idea of agonist therapy for treating cocaine addiction. This strategy involves administration of stimulant-like medications (eg, monoamine releasers) to alleviate withdrawal symptoms and prevent relapse. A major limitation of this approach is that many candidate medicines possess significant abuse potential because of activation of mesolimbic dopamine (DA) neurons in central nervous system reward circuits. Previous data suggest that serotonin (5-HT) neurons can provide an inhibitory influence over mesolimbic DA neurons. Thus, it might be predicted that the balance between DA and 5-HT transmission is important to consider when developing medications with reduced stimulant side effects. In this article, we discuss several issues related to the development of dual DA/5-HT releasers for the treatment of substance use disorders. First, we discuss evidence supporting the existence of a dual deficit in DA and 5-HT function during withdrawal from chronic cocaine or alcohol abuse. Then we summarize studies that have tested the hypothesis that 5-HT neurons can dampen the effects mediated by mesolimbic DA. For example, it has been shown that pharmacological manipulations that increase extracellular 5-HT attenuate stimulant effects produced by DA release, such as locomotor stimulation and self-administration behavior. Finally, we discuss our recently published data about PAL-287 (naphthylisopropylamine), a novel non-amphetamine DA-/5-HT-releasing agent that suppresses cocaine self-administration but lacks positive reinforcing properties. It is concluded that DA/5-HT releasers might be useful therapeutic adjuncts for the treatment of cocaine and alcohol addiction, obesity, and even attention deficit disorder and depression.
我们一直倡导使用激动剂疗法治疗可卡因成瘾。该策略包括给予类似兴奋剂的药物（如单胺释放剂）以减轻戒断症状并预防复发。这种方法的一个主要局限性在于，许多候选药物由于激活中枢神经系统奖赏回路中的中脑边缘多巴胺（DA）神经元而具有显著的滥用潜力。先前的数据表明，血清素（5-HT）神经元可对中脑边缘DA神经元产生抑制作用。因此，可以预测，在开发具有减轻兴奋剂副作用的药物时，考虑DA和5-HT传递之间的平衡很重要。在本文中，我们讨论了与开发用于治疗物质使用障碍的DA/5-HT双重释放剂相关的几个问题。首先，我们讨论支持在慢性可卡因或酒精滥用戒断期间DA和5-HT功能存在双重缺陷的证据。然后，我们总结了检验5-HT神经元可减弱中脑边缘DA介导的效应这一假设的研究。例如，已表明增加细胞外5-HT的药理学操作可减弱由DA释放产生的兴奋剂效应，如运动刺激和自我给药行为。最后，我们讨论了我们最近发表的关于PAL-287（萘基异丙胺）的数据，这是一种新型非苯丙胺类DA-/5-HT-释放剂，可抑制可卡因自我给药但缺乏正性强化特性。得出的结论是，DA/5-HT释放剂可能是治疗可卡因和酒精成瘾、肥胖症甚至注意力缺陷障碍和抑郁症的有用治疗辅助药物。
