The present experiments investigated the ability of LY392098, a novel positive allosteric modulator of AMPA receptors, to potentiate AMPA receptor-mediated currents of neurons in the prefrontal cortex (PFC). Co-application of LY392098 (0.03-10 microM) with AMPA (5 microM) enhanced current through AMPA receptor/channels in acutely isolated PFC neurons in a concentration-dependent manner. Estimates of the potency (EC(50)) and efficacy for LY392098 yielded an EC(50) value of 1.7+/-0.5 microM and a maximal potentiation of a 31.0+/-4.1-fold increase relative to current evoked by AMPA alone. The potentiation was activity-dependent, becoming evident only in the presence of agonist, and time-dependent, continuously developing over prolonged application times. An extracellular site of action was inferred by the absence of potentiation when the compound was applied intracellularly. LY392098 also increased the potency of agonist for the receptor by approximately sevenfold. Selectivity assays showed that the effects of LY392098 were exclusive for AMPA receptors, having no activity at N-methyl-D-aspartate (NMDA) receptors in PFC neurons. Extracellular recordings from single PFC neurons in vivo showed that administration of LY392098 (0.001-10 microg/kg, i.v.) enhanced the probability of evoked action potential discharge in response to stimulation of glutamatergic 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 centrally active positive modulator of native AMPA receptors.