Dooley D J, Donovan C M, Pugsley T A
Department of Neuroscience Therapeutics, Pfizer Global Research & Development, Ann Arbor, Michigan 48105, USA.
J Pharmacol Exp Ther. 2000 Dec;295(3):1086-93.
Gabapentin (GBP; Neurontin) has proven efficacy in several neurological and psychiatric disorders yet its mechanism of action remains elusive. This drug, and the related compounds pregabalin [PGB; CI-1008, S-(+)-3-isobutylgaba] and its enantiomer R-(-)-3-isobutylgaba, were tested in an in vitro superfusion model of stimulation-evoked neurotransmitter release using rat neocortical slices prelabeled with [(3)H]norepinephrine ([(3)H]NE). The variables addressed were stimulus type (i.e., electrical, K(+), veratridine) and intensity, concentration dependence, onset and reversibility of action, and commonality of mechanism. Both GBP and PGB inhibited electrically and K(+)-evoked [(3)H]NE release, but not that induced by veratridine. Inhibition by these drugs was most pronounced with the K(+) stimulus, allowing determination of concentration-effect relationships (viz., 25 mM K(+) stimulus: GBP IC(50) = 8.9 microM, PGB IC(50) = 11.8 microM). R-(-)-3-Isobutylgaba was less effective than PGB to decrease stimulation-evoked [(3)H]NE release. Other experiments with GBP demonstrated the dependence of [(3)H]NE release inhibition on optimal stimulus intensity. The inhibitory effect of GBP increased with longer slice exposure time before stimulation, and reversed upon washout. Combination experiments with GBP and PGB indicated a similar mechanism of action to inhibit K(+)-evoked [(3)H]NE release. GBP and PGB are concluded to act in a comparable, if not identical, manner to preferentially attenuate [(3)H]NE release evoked by stimuli effecting mild and prolonged depolarizations. This type of modulation of neurotransmitter release may be integral to the clinical pharmacology of these drugs.
加巴喷丁（GBP；Neurontin）已被证明对多种神经和精神疾病有效，但其作用机制仍不清楚。使用预先用[³H]去甲肾上腺素（[³H]NE）标记的大鼠新皮层切片，在刺激诱发神经递质释放的体外灌流模型中对该药物以及相关化合物普瑞巴林[PGB；CI-1008，S-(+)-3-异丁基 GABA]及其对映体 R-(-)-3-异丁基 GABA 进行了测试。研究的变量包括刺激类型（即电刺激、K⁺、藜芦碱）和强度、浓度依赖性、作用的起效和可逆性以及作用机制的共性。GBP 和 PGB 均抑制电刺激和 K⁺诱发的[³H]NE 释放，但不抑制藜芦碱诱导的释放。这些药物对 K⁺刺激的抑制作用最为明显，从而能够确定浓度-效应关系（即，25 mM K⁺刺激：GBP 的半数抑制浓度（IC₅₀）= 8.9 μM，PGB 的 IC₅₀ = 11.8 μM）。R-(-)-3-异丁基 GABA 在减少刺激诱发的[³H]NE 释放方面比 PGB 效果差。其他关于 GBP 的实验表明[³H]NE 释放抑制依赖于最佳刺激强度。GBP 的抑制作用随着刺激前切片暴露时间延长而增强，并在洗脱后逆转。GBP 和 PGB 的联合实验表明它们在抑制 K⁺诱发的[³H]NE 释放方面具有相似的作用机制。得出的结论是，GBP 和 PGB 的作用方式相似（即便不完全相同），优先减弱由引起轻度和长时间去极化的刺激所诱发的[³H]NE 释放。这种神经递质释放的调节类型可能是这些药物临床药理学的重要组成部分。
