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 microM) 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.
Di Angelantonio
Silvia
S
Laboratorio di Neurologia Sperimentale, IRCCS-Fondazione Santa Lucia, Via Ardeatina 306, Rome 00179, Italy. s.diangelantonio@hsantalucia.it
Bernardi
Giorgio
G
Mercuri
Nicola B
NB
D000818:Animals; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D000077265:Donepezil; D004298:Dopamine / Q000502:physiology*; D004594:Electrophysiology; D066298:In Vitro Techniques; D007189:Indans / Q000494:pharmacology*; D007306:Insecticides / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects; D009474:Neurons / Q000187:drug effects*; D009538:Nicotine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D018722:Nicotinic Agonists / Q000494:pharmacology; D018697:Nootropic Agents / Q000494:pharmacology*; D009946:Organothiophosphorus Compounds / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D010880:Piperidines / Q000494:pharmacology*; D051381:Rats; D011978:Receptors, Nicotinic / Q000187:drug effects*; D013378:Substantia Nigra / Q000166:cytology / Q000187:drug effects*; D013569:Synapses / Q000187:drug effects; D009435:Synaptic Transmission / Q000187:drug effects
D002800:Cholinesterase Inhibitors; D007189:Indans; D007306:Insecticides; D018722:Nicotinic Agonists; D018697:Nootropic Agents; D009946:Organothiophosphorus Compounds; D010880:Piperidines; D011978:Receptors, Nicotinic; D009538:Nicotine; D000077265:Donepezil; C014655:methamidophos; D004298:Dopamine