Senior Staff Scientist, Director of Neural Physiology Laboratory, Division of Neurology, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, 350 West Thomas Rd., Phoenix, AZ 85013-4496, USA.
J Pharmacol Exp Ther. 2010 Nov;335(2):401-8. doi: 10.1124/jpet.110.171108. Epub 2010 Aug 5.
Lamotrigine (LTG), an anticonvulsive drug, is often used for the treatment of a variety of epilepsies. In addition to block of sodium channels, LTG may act on other targets to exert its antiepileptic effect. In the present study, we evaluated the effects of LTG on neuronal nicotinic acetylcholine receptors (nAChRs) using the patch-clamp technique on human α4β2-nAChRs heterologously expressed in the SH-EP1 cell line and on native α4β2-nAChRs in dopaminergic (DA) neurons in rat ventral tegmental area (VTA). In SH-EP1 cells, LTG diminished the peak and steady-state components of the inward α4β2-nAChR-mediated currents. This effect exhibited concentration-, voltage- and use-dependent behavior. Nicotine dose-response curves showed that in the presence of LTG, the nicotine-induced maximal current was reduced, suggesting a noncompetitive inhibition. These findings suggest that LTG inhibits human neuronal α4β2-nAChR function through an open-channel blocking mechanism. LTG-induced inhibition in α4β2-nAChRs was more profound when preceded by a 2-min pretreatment, after which the nicotine-induced current was reduced even without coapplication of LTG, suggesting that LTG is also able to inhibit α4β2-nAChRs without channel activation. In freshly dissociated VTA DA neurons, LTG inhibited α4β2-nAChR-mediated currents but did not affect glutamate- or GABA-induced currents, indicating that LTG selectively inhibits nAChR function. Collectively, our data suggest that the neuronal α4β2-nAChR is likely an important target for mediating the anticonvulsive effect of LTG and the blockade of α4β2-nAChR possibly underlying the mechanism through which LTG effectively controls some types of epilepsy, such as autosomal dominant nocturnal frontal lobe epilepsy or juvenile myoclonic epilepsy.
拉莫三嗪（LTG）是一种抗惊厥药物，常用于治疗各种癫痫。除了阻断钠通道外，LTG 可能还作用于其他靶点发挥抗癫痫作用。本研究采用膜片钳技术，在人 SH-EP1 细胞系中表达的α4β2 型烟碱型乙酰胆碱受体（nAChR）和大鼠腹侧被盖区（VTA）多巴胺能（DA）神经元中的内源性α4β2-nAChR 上，评估了 LTG 对神经元型 nAChR 的影响。在 SH-EP1 细胞中，LTG 减少了内向α4β2-nAChR 介导电流的峰值和稳态成分。这种作用表现出浓度、电压和使用依赖性。烟碱剂量反应曲线表明，在 LTG 存在的情况下，烟碱诱导的最大电流减少，表明非竞争性抑制。这些发现表明，LTG 通过开放通道阻断机制抑制人神经元α4β2-nAChR 功能。当用 2 分钟的预处理预先处理后，LTG 诱导的抑制作用更为明显，之后即使没有同时应用 LTG，烟碱诱导的电流也会减少，表明 LTG 也能够在不激活通道的情况下抑制α4β2-nAChR。在新鲜分离的 VTA DA 神经元中，LTG 抑制α4β2-nAChR 介导的电流，但不影响谷氨酸或 GABA 诱导的电流，表明 LTG 选择性抑制 nAChR 功能。综上所述，我们的数据表明，神经元α4β2-nAChR 可能是介导 LTG 抗惊厥作用的重要靶点，α4β2-nAChR 的阻断可能是 LTG 有效控制某些类型癫痫（如常染色体显性夜间额叶癫痫或青少年肌阵挛性癫痫）的机制之一。
