Lenkey N, Karoly R, Kiss J P, Szasz B K, Vizi E S, Mike A
Department of Pharmacology, Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary.
Mol Pharmacol. 2006 Dec;70(6):2052-63. doi: 10.1124/mol.106.026419. Epub 2006 Sep 19.
The effect of monoamine uptake inhibitor-type antidepressants on sodium channels of hippocampal neurons was investigated. Members of the tricyclic group of antidepressants are known to modify multiple targets, including sodium channels, whereas selective serotonin-reuptake inhibitors (SSRIs) are regarded as highly selective compounds, and their effect on sodium channels was not investigated in detail. In this study, a representative member of each group was chosen: the tricyclic antidepressant desipramine and the SSRI fluoxetine. The drugs were roughly equipotent use-dependent inhibitors of sodium channels, with IC(50) values approximately 100 microM at -150 mV holding potential, and approximately 1 microM at -60 mV. We suggest that therapeutic concentrations of antidepressants affect neuronal information processing partly by direct, activity-dependent inhibition of sodium channels. As for the mechanism of inhibition, use-dependent inhibition by antidepressants was believed to be due to a preferential affinity to the fast-inactivated state. Using a voltage and perfusion protocol by which relative affinities to fast-versus slow-inactivated states could be assessed, we challenged this view and found that the affinity of both drugs to slowinactivated state(s) was higher. We propose a different mechanism of action for these antidepressants, in which slow rather than fast inactivation plays the dominant role. This mechanism is similar but not equivalent with the novel mechanism of usedependent sodium channel inhibition previously described by our group (Neuroscience 125:1019-1028, 2004; Neuroreport 14:1945-1949, 2003). Our results suggest that different drugs can produce use-dependent sodium channel inhibition by different mechanisms.
研究了单胺摄取抑制剂类抗抑郁药对海马神经元钠通道的影响。已知三环类抗抑郁药可作用于多个靶点，包括钠通道，而选择性5-羟色胺再摄取抑制剂（SSRI）则被视为高选择性化合物，尚未对其对钠通道的影响进行详细研究。在本研究中，选取了每组的一个代表性药物：三环类抗抑郁药地昔帕明和SSRI氟西汀。这两种药物均为大致等效的钠通道使用依赖性抑制剂，在-150 mV钳制电位下的IC（50）值约为100 μM，在-60 mV时约为1 μM。我们认为，抗抑郁药的治疗浓度部分通过对钠通道的直接、活性依赖性抑制来影响神经元信息处理。至于抑制机制，抗抑郁药的使用依赖性抑制被认为是由于对快速失活状态具有优先亲和力。我们采用一种可评估对快速与缓慢失活状态相对亲和力的电压和灌流方案，对这一观点提出质疑，并发现两种药物对缓慢失活状态的亲和力更高。我们提出了这些抗抑郁药的一种不同作用机制，其中起主导作用的是缓慢而非快速失活。该机制与我们小组先前描述的钠通道使用依赖性抑制新机制相似但不等同（《神经科学》125:1019 - 1028，2004；《神经报告》14:1945 - 1949，2003）。我们的结果表明，不同药物可通过不同机制产生钠通道使用依赖性抑制。
