PT - JOURNAL ARTICLE AU - Moriguchi, Shigeki AU - Marszalec, William AU - Zhao, Xilong AU - Yeh, Jay Z. AU - Narahashi, Toshio TI - Potentiation of <em>N</em>-Methyl-<span class="sc">d</span>-aspartate-Induced Currents by the Nootropic Drug Nefiracetam in Rat Cortical Neurons AID - 10.1124/jpet.103.050823 DP - 2003 Oct 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - 160--167 VI - 307 IP - 1 4099 - http://jpet.aspetjournals.org/content/307/1/160.short 4100 - http://jpet.aspetjournals.org/content/307/1/160.full SO - J Pharmacol Exp Ther2003 Oct 01; 307 AB - Nefiracetam is a new pyrrolidone nootropic drug being developed for the treatment of Alzheimer's type and post-stroke vascular-type dementia. In the brain of Alzheimer's disease patients, down-regulation of both cholinergic and glutamatergic systems has been found and is thought to play an important role in impairment of cognition, learning and memory. We have previously shown that the activity of neuronal nicotinic acetylcholine receptors is potently augmented by nefiracetam. The present study was undertaken to elucidate the mechanism of action of nefiracetam on glutamatergic receptors. Currents were recorded from rat cortical neurons in long-term primary culture using the whole-cell patch-clamp technique at a holding potential of –70 mV in Mg2+-free solutions. N-Methyl-d-aspartate (NMDA)-evoked currents were greatly and reversibly potentiated by bath application of nefiracetam resulting in a bell-shaped dose-response curve. The minimum effective nefiracetam concentration was 1 nM, and the maximum potentiation to 170% of the control was produced at 10 nM. Nefiracetam potentiation occurred at high NMDA concentrations that evoked the saturated response, and in a manner independent of NMDA concentrations ranging from 3 to 1,000 μM. Glycine at 3 μM potentiated NMDA currents but this effect was attenuated with an increasing concentration of nefiracetam from 1 to 10,000 nM. 7-Chlorokynurenic acid at 1 μM prevented nefiracetam from potentiating NMDA currents. Nefiracetam at 10 nM shifted the dose-response relationship for the 7-chlorokynurenic acid inhibition of NMDA currents in the direction of higher concentrations. α-Amino-3-hydroxy-5-methylisoxazole-4-propionic acid- and kainate-induced currents were not significantly affected by application of 10 nM nefiracetam. It was concluded that nefiracetam potentiated NMDA currents through interactions with the glycine binding site of the NMDA receptor. The American Society for Pharmacology and Experimental Therapeutics