The Anticonvulsive Drug Lamotrigine Blocks Neuronal α4β2 Nicotinic Acetylcholine Receptors

Abstract

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 ␣4␤2-nAChRs heterologously expressed in the SH-EP1 cell line and on native ␣4␤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 ␣4␤2-nAChR-mediated currents. This effect exhibited concentration-, voltage-and use-dependent behavior. Nicotine doseresponse 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 ␣4␤2-nAChR function through an openchannel blocking mechanism. LTG-induced inhibition in ␣4␤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 ␣4␤2-nAChRs without channel activation. In freshly dissociated VTA DA neurons, LTG inhibited ␣4␤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 ␣4␤2-nAChR is likely an important target for mediating the anticonvulsive effect of LTG and the blockade of ␣4␤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.

Down-Regulation of Hippocampal Genes Regulating Dopaminergic, GABAergic, and Glutamatergic Function Following Combined Neonatal Phencyclidine and Post-Weaning Social Isolation of Rats as a Neurodevelopmental Model for Schizophrenia

“…In addition, lamotrigine has weak inhibitory effects at the 5-HT 3 , 5-HT 1A , and nicotinic acetylcholine receptors (Bourin et al, 2005; Zheng et al, 2010). Although not approved to treat schizophrenia, clinical studies have noted lamotrigine may improve some symptoms in a clozapine-resistant patient population (Goff, 2009; Tiihonen et al, 2009).…”

Pathologic role of neuronal nicotinic acetylcholine receptors in epileptic disorders: implication for pharmacological interventions

“…The nicotine-induced maximal current was also reduced in the presence of lamotrigine (Zheng et al, 2010). In freshly dissociated ventral tegmental area dopaminergic neurons, lamotrigine inhibited α 4 β 2 nAChRs-mediated currents but did not affect glutamate-or GABA-induced currents, indicating that lamotrigine selectively inhibits α 4 β 2 nAChR function (Zheng et al, 2010). These data may raise the possibility that lamotrigine could be beneficial in the treatment of seizures in ADNFLE.…”

“…Using the patch-clamp technique on human α 4 β 2 nAChRs heterologously expressed in the SH-EP1 cell line and on native α 4 β 2 nAChRs in dopaminergic neurons in rat ventral tegmental area, Zheng et al (2010) have recently revealed that lamotrigine is able to diminish the peak and steadystate components of the inward α 4 β 2 nAChR-mediated currents in a concentration-, voltage-, and use-dependent manner. The nicotine-induced maximal current was also reduced in the presence of lamotrigine (Zheng et al, 2010). In freshly dissociated ventral tegmental area dopaminergic neurons, lamotrigine inhibited α 4 β 2 nAChRs-mediated currents but did not affect glutamate-or GABA-induced currents, indicating that lamotrigine selectively inhibits α 4 β 2 nAChR function (Zheng et al, 2010).…”

“…A single lamotrigine molecule appears to be involved because the duration of the closed state did not increase with lamotrigine concentration (Vallés et al, 2008). Using the patch-clamp technique on human α 4 β 2 nAChRs heterologously expressed in the SH-EP1 cell line and on native α 4 β 2 nAChRs in dopaminergic neurons in rat ventral tegmental area, Zheng et al (2010) have recently revealed that lamotrigine is able to diminish the peak and steadystate components of the inward α 4 β 2 nAChR-mediated currents in a concentration-, voltage-, and use-dependent manner. The nicotine-induced maximal current was also reduced in the presence of lamotrigine (Zheng et al, 2010).…”

An overview on antiepileptic drugs

“…Recent studies further suggested that the neuronal α4β2-nAChR (neuronal nicotinic acetylcholine receptor) is likely an important target. The blockade of α4β2-nAChR might represent the mechanism through which LTG effectively controls some types of epilepsy such as autosomal dominant nocturnal frontal lobe epilepsy or juvenile myoclonic epilepsy (27). Among the adverse effects, idiosyncratic drug reactions, especially skin rashes are considered fatal and may require discontinuation of the drug.…”