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

The effects of nefiracetam (DM-9384) on the neuronal nicotinic acetylcholin e (ACh) receptor-channel were studied by the whole-cell patch clamp techniq ue 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 AC h and suppressed those induced by high concentrations (100-1000 mu M) of AC h. 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 lo w concentration (10 mu M) of ACh. The rate of desensitization of ACh-induce d 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 n ot the protein kinase C inhibitor calphostin C (0.5 mu M), abolished the ne firacetam 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 nefi racetam. (C) 1999 Elsevier Science B.V. All rights reserved.