Modulation of the neuronal nicotinic acetylcholine receptor-channel by the nootropic drug nefiracetam

• Published in: Brain research 1999-03, Vol.822 (1), p.72-79
• Main Authors: Oyaizu, Miki, Narahashi, Toshio
• Format: Article
• Language: English
• Subjects: Acetylcholine - pharmacology; Acetylcholine receptor; Animals; Biological and medical sciences; Carbazoles; Cyclic AMP-Dependent Protein Kinases - metabolism; Dose-Response Relationship, Drug; Enzyme Inhibitors - pharmacology; G protein; GTP-Binding Proteins - metabolism; Indoles - pharmacology; Medical sciences; Membrane Potentials - drug effects; Naphthalenes - pharmacology; Nefiracetam; Neurons - chemistry; Neurons - enzymology; Neuropharmacology; Nootropic Agents - pharmacology; Nootropic drug; Patch-Clamp Techniques; PC12 cell; PC12 Cells; Pertussis Toxin; Pharmacology. Drug treatments; Protein kinase; Protein Kinase C - antagonists & inhibitors; Protein Kinase C - metabolism; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease); Psychology. Psychoanalysis. Psychiatry; Psychopharmacology; Pyrroles - pharmacology; Pyrrolidinones - pharmacology; Rats; Receptors, Nicotinic - physiology; Signal Transduction - drug effects; Virulence Factors, Bordetella - pharmacology
• ISSN: 0006-8993; 1872-6240
• DOI: 10.1016/S0006-8993(99)01077-X

The effects of nefiracetam (DM-9384) on the neuronal nicotinic acetylcholine (ACh) receptor-channel were studied by the whole-cell patch clamp technique using PC12 cells. Nefiracetam had a dual effect on ACh-induced currents: it augmented the currents induced by low concentrations (10–30 μM) of ACh and suppressed those induced by high concentrations (100–1000 μM) of ACh. These effects were reversible after washing with drug-free solution. The stimulating effect of nefiracetam was clearly observed at a concentration of 10 μM, and slight increases in currents were detected even at 0.1 μM or 1 μM. Nefiracetam at 100 μM suppressed the currents induced by a low concentration (10 μM) of ACh. The rate of desensitization of ACh-induced current was greatly accelerated by nefiracetam, and this effect could not be reversed by washing with drug-free solution. When added to the internal pipette solution, the protein kinase A inhibitor KT 5720 (0.6 μM), but not the protein kinase C inhibitor calphostin C (0.5 μM), abolished the nefiracetam stimulation of the ACh receptor. Pre-incubation of cells with 200 ng/ml pertussis toxin for 24 h also abolished the nefiracetam action. Thus, the nefiracetam modulation of the neuronal nicotinic ACh receptor-channel is exerted via G proteins and protein kinase A. The stimulation of the ACh receptor may be directly related to the cognitive enhancing action of nefiracetam.