This review describes interactions between compounds, primarily dihydropyridines, that block L-type calcium channels and drugs that cause dependence, and the potential importance of these interactions. The main dependence-inducing drugs covered are alcohol, psychostimulants, opioids, and nicotine. In preclinical studies, L-type calcium channel blockers prevent or reduce important components of dependence on these drugs, particularly their reinforcing actions and the withdrawal syndromes. The channel blockers also reduce the development of tolerance and/or sensitization, and they have no intrinsic dependence liability. In some instances, their effects include reversal of brain changes established during drug dependence. Prolonged treatment with alcohol, opioids, psychostimulant drugs, or nicotine causes upregulation of dihydropyridine binding sites. Few clinical studies have been carried out so far, and reports are conflicting, although there is some evidence of effectiveness of L-channel blockers in opioid withdrawal. However, the doses of L-type channel blockers used clinically so far have necessarily been limited by potential cardiovascular problems and may not have provided sufficient central levels of the drugs to affect neuronal dihydropyridine binding sites. New L-type calcium channel blocking compounds are being developed with more selective actions on subtypes of L-channel. The preclinical evidence suggests that L-type calcium channels may play a crucial role in the development of dependence to different types of drugs. Mechanisms for this are proposed, including changes in the activity of mesolimbic dopamine neurons, genomic effects, and alterations in synaptic plasticity. Newly developed, more selective L-type calcium channel blockers could be of considerable value in the treatment of drug dependence.

中文翻译：

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L型钙通道阻滞剂：一种潜在的药物依赖性新治疗方法


这篇综述描述了阻断 L 型钙通道的化合物（主要是二氢吡啶）与引起依赖性的药物之间的相互作用，以及这些相互作用的潜在重要性。涵盖的主要引起依赖性的药物是酒精、精神兴奋剂、阿片类药物和尼古丁。在临床前研究中，L 型钙通道阻滞剂可预防或减少对这些药物依赖的重要组成部分，特别是其增强作用和戒断综合征。通道阻断剂还可以减少耐受性和/或致敏性的发展，并且它们没有内在的依赖性倾向。在某些情况下，它们的作用包括逆转药物依赖期间建立的大脑变化。长期使用酒精、阿片类药物、精神兴奋药物或尼古丁治疗会导致二氢吡啶结合位点上调。尽管有一些证据表明 L 通道阻滞剂对阿片类药物戒断有效，但迄今为止进行的临床研究很少，且报告相互矛盾。然而，迄今为止临床上使用的L型通道阻滞剂的剂量必然受到潜在心血管问题的限制，并且可能无法提供足够的药物中心水平来影响神经元二氢吡啶结合位点。新型 L 型钙通道阻断化合物正在开发中，对 L 通道亚型具有更强的选择性作用。临床前证据表明，L 型钙通道可能在不同类型药物依赖性的形成中发挥至关重要的作用。提出了这一机制，包括中脑边缘多巴胺神经元活性的变化、基因组效应和突触可塑性的改变。 新开发的更具选择性的 L 型钙通道阻滞剂在治疗药物依赖方面可能具有相当大的价值。