Donepezil modulates nicotinic receptors of substantia nigra dopaminergic neurones

1 The effects of donepezil, one of the most common cholinesterase inhibitors used for treatment of Alzheimer's disease, were studied on nicotinic receptors (nAChRs)-mediated postsynaptic currents, in dopaminergic neurons of the substantia nigra pars compacta, using the patch-clamp recording technique in slice preparations. 2 Donepezil (10-100 muM) selectively and reversibly depressed nicotine currents, induced by brief puffer pulses, through a glass micropipette positioned above the slice. 3 The peak amplitude fading of the responses generated by repeated test applications of low doses of nicotine was accelerated by donepezil, while it slowed the recovery of nicotine currents after a large, desensitising, dose of the same agonist. 4 Donepezil depressed even maximal responses to nicotine, revealing a noncompetitive mechanism of action; moreover, the inhibition of nAChRs was voltage and time independent. 5 Pretreatment with vesamicol or methamidophos did not prevent the reduction of nicotine-induced currents. The data indicated direct effect on nAChR, independent from the activity of donepezil as cholinesterase inhibitor.