The anticonvulsive drug Lamotrigine blocks neuronal alpha-4beta2-nicotinic acetylcholine receptors.

ZHENG, C.; YANG, K.; WANG, M.-Y.; VALLÉS, S.; LUKAS, R.J.; BARRANTES FJ; WU, J.

JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS

AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS

Año: 2010 vol. 335 p. 401 - 408

0022-3565

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 also 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 á4â2-nAChRs heterologously expressed in the SH-EP1 cell line and on native á4â2-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 á4â2-nAChR-mediated currents. This  effect exhibited concentration-, voltage- and use-dependent behavior. These findings suggest that LTG inhibits human neuronal á4â2-nAChR function through an open-channel blocking mechanism. LTG-induced inhibition in á4â2 nAChRs was more profound when preceded by a 2 min pre-treatment, after which the nicotine-induced current was reduced even without co-application of LTG, , suggesting that LTG is also able to inhibit á4â2-nAChRs without channel activation. In freshly dissociated VTA DA neurons, LTG inhibited á4â2-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 á4â2-nAChR is likely an important target for mediating LTG’s anticonvulsive effect, and the blockade of á4â2-nAChR possibly underlying the mechanism through which LTG effectively controls autosomal dominant nocturnal frontal lobe epilepsy.