LY392098, a novel AMPA receptor potentiator: electrophysiological studies in prefrontal cortical neurons

The present experiments investigated the ability of LY392098, a novel posit ive allosteric modulator of AMPA receptors, to potentiate AMPA receptor-med iated currents of neurons in the prefrontal cortex (PFC). Go-application of LY392098 (0.03-10 muM) with AMPA (5 muM) enhanced current through AMPA rec eptor/channels in acutely isolated PFC neurons in a concentration-dependent manner. Estimates of the potency (EC50) and efficacy for LY392098 yielded an EC50 value of 1.7 +/-0.5 muM and a maximal potentiation of a 31.0 +/-4.1 -fold increase relative to current evoked by AMPA alone. The potentiation w as activity-dependent, becoming evident only in the presence of agonist, an d time-dependent, continuously developing over prolonged application times. An extracellular site of action was inferred by the absence of potentiatio n when the compound was applied intracellularly. LY392098 also increased th e potency of agonist for the receptor by approximately sevenfold. Selectivi ty assays showed that the effects of LY392098 were exclusive for AMPA recep tors, having no activity at N-methyl-D-aspartate (NMDA) receptors in PFC ne urons. Extracellular recordings from single PEG neurons in vivo showed that administration of LY392098 (0.001-10 mug/kg, i.v.) enhanced the probabilit y of evoked action potential discharge in response to stimulation of glutam atergic afferents from the ventral subiculum of the hippocampal formation. Spontaneous activity of PFC neurons was also increased. Collectively, these results demonstrate that LY392098 is a highly potent, selective and centra lly active positive modulator of native AMPA receptors. (C) 2001 Elsevier S cience Ltd. All rights reserved.