The Anticonvulsive Drug Lamotrigine Blocks Neuronal α4β2 Nicotinic Acetylcholine Receptors

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 alpha 4 beta 2-nAChRs heterologously expressed in the SH-EP1 cell line and on native alpha 4 beta 2-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 alpha 4 beta 2-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 alpha 4 beta 2-nAChR function through an open-channel blocking mechanism. LTG-induced inhibition in alpha 4 beta 2-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 alpha 4 beta 2-nAChRs without channel activation. In freshly dissociated VTA DA neurons, LTG inhibited alpha 4 beta 2-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 alpha 4 beta 2-nAChR is likely an important target for mediating the anticonvulsive effect of LTG and the blockade of alpha 4 beta 2-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.