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

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 mu M) of ACh and suppressed those induced by high concentrations (100-1000 mu M) 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 mu M, and slight increases in currents were detected even at 0.1 mu M or 1 mu M. Nefiracetam at 100 mu M suppressed the currents induced by a low concentration (10 mu M) 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 mu M), but not the protein kinase C inhibitor calphostin C (0.5 mu M), abolished the nefiracetam stimulation of the ACh receptor. Pie-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. (C) 1999 Elsevier Science B.V. All rights reserved.