Johnson Bankole A
Department of Psychiatric Medicine, University of Virginia, Charlottesville, VA 22908, USA.
CNS Drugs. 2005;19(10):873-96. doi: 10.2165/00023210-200519100-00005.
Neuroscientific developments have promulgated interest in developing efficacious medications for the treatment of substance dependence. Previous pharmacological strategies that involve the use of relatively specific medications to alter corticomesolimbic dopaminergic neuronal activity--the critical pathway for expression of the reinforcing effects of abused drugs--have yielded modest efficacy in the treatment of alcohol dependence, and no medication has been established as a treatment for cocaine dependence. Since corticomesolimbic dopaminergic neurons interact with other neurotransmitters that modulate the effects of dopamine in the nucleus accumbens, would it not be possible to control these dopaminergic effects more reliably with a medication that acts contemporaneously on more than one neuromodulator of dopaminergic function? Further, since the long-term use of either alcohol or cocaine results in neuronal adaptations as a result of sensitisation, would the chances of effective therapy not be bolstered by administering a medication that was also able to mitigate these chronic effects? Thus, a new conceptual approach is needed. My proposal is that a medication--in this case topiramate--that principally potentiates inhibitory GABA(A) receptor-mediated input and antagonises excitatory glutamatergic afferents to the corticomesolimbic dopaminergic system should have therapeutic potential in treating either alcohol or cocaine dependence or perhaps both. This is because the principal neurochemical effects of topiramate would not only serve to decrease the acute reinforcing effects of alcohol or cocaine, but might also facilitate cessation of their use following a period of long-term use by decreasing neuronal sensitisation. This overview highlights the scientific concepts and clinical evidence for the development of topiramate in the treatment of alcohol dependence and introduces preliminary evidence to indicate that it might also have utility in treating cocaine dependence. Finally, to place the material on topiramate in context, information has been included on the utility and development of other medications that modulate GABA- or glutamate-mediated neuronal systems for the treatment of alcohol or cocaine dependence.
神经科学的发展激发了人们对开发有效药物治疗物质依赖的兴趣。以往的药理学策略是使用相对特异性的药物来改变皮质-中脑边缘多巴胺能神经元的活动——这是滥用药物强化作用表达的关键途径——在治疗酒精依赖方面疗效一般，且尚无药物被确认为可治疗可卡因依赖。由于皮质-中脑边缘多巴胺能神经元与其他调节伏隔核中多巴胺作用的神经递质相互作用，那么使用一种能同时作用于多种多巴胺能功能神经调节剂的药物，是否有可能更可靠地控制这些多巴胺能效应呢？此外，由于长期使用酒精或可卡因都会因敏感化导致神经元适应性变化，那么使用一种也能减轻这些慢性影响的药物，有效治疗的几率是否会增加呢？因此，需要一种新的概念性方法。我的提议是，一种药物——在这种情况下是托吡酯——主要增强抑制性GABA(A)受体介导的输入并拮抗皮质-中脑边缘多巴胺能系统的兴奋性谷氨酸能传入，应该在治疗酒精或可卡因依赖或两者兼治方面具有治疗潜力。这是因为托吡酯的主要神经化学作用不仅会降低酒精或可卡因的急性强化作用，还可能通过降低神经元敏感化促进长期使用后停止使用这些药物。本综述强调了托吡酯治疗酒精依赖的科学概念和临床证据，并介绍了初步证据表明它可能对治疗可卡因依赖也有用。最后，为了将关于托吡酯的内容置于背景中，还纳入了其他调节GABA或谷氨酸介导的神经元系统用于治疗酒精或可卡因依赖的药物的效用和开发信息。
