Among many other physiological processes, melatonin –a hormone that is produced and released by the pineal gland– has been involved in modulation of central and peripheral cholinergic activity (Barajas-Lopez et al. 1996; Markus et al. 2003), albeit data on the effects of this hormone on nicotinic channel activity are very scarce. Neuronal nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels widely expressed throughout the vertebrate CNS, including the cerebellum. Functional nAChRs are also expressed by cerebellar granule neurons (CGNs) in culture (Fucile et al. 2004). We have used electrophysiological and Ca²⁺ fluorescence techniques to determine whether low concentrations of melatonin affected nicotine-induced currents in rat cultured CGNs.

Melatonin significantly reduced the amplitude of whole-cell inward currents evoked by nicotine (50 micromolar) in a dose-dependent manner (IC50 = 0.6 pM). The receptor's apparent affinity, and rise time and decay course of nicotine-evoked currents were hardly altered by melatonin. This inhibitory effect was significantly reduced by luzindole, a competitive antagonist of both MT1 and MT2 melatonin membrane-receptors. We conclude that melatonin, at picomolar and nanomolar concentrations, blocks nAChR currents in cultured CGN at least partially by a mechanism that involves binding to melatonin membrane-receptors. We suggest that melatonin may directly participate in modulation of nicotinic receptors, coupling cholinergic activity to rhythmic circadian levels of melatonin. This work was supported by grants GRJ05-07 and GRJ06-06 from the University of Alicante.