Attention has focused on drugs that modulate AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid) receptors because of their potential for enhancing memory and treating certain pathologies that involve glutamatergic neurotransmission. The aim of this study was to compare and contrast the functionality of positive allosteric modulators of AMPA receptors in the hippocampus and medial prefrontal cortex. Electrically stimulated EPSPs (excitatory postsynaptic potential) in the hippocampus were augmented by CX516 [(1-quinoxaline-6-ylcarbonyl)piperidine], aniracetam and 1-BCP [(1-(1,3-benzodioxol-5-ylcarbonyl)piperidine] and not by cyclothiazide. Using grease gap electrophysiology, it was found that the mode of application dramatically altered the effect of the modulators of AMPA-induced depolarization. When added simultaneously with AMPA, aniracetam, 1-BCP and CX516 augmented the response in the frontal cortex. However, in the hippocampus, only aniracetam and cyclothiazide augmented the response when simultaneously added to AMPA. Therefore, in addition to regional variations, there appears to be differences in modulator response dependent upon whether a response is generated endogenously or exogenously by AMPA.

The effects of several glycine antagonists at the strychnine-insensitive site on N-methyl-D-aspartate (NMDA) receptors in an acute in vitro electrophysiological model of ischemia in the rat hippocampus were studied. Hippocampal slices were subjected to 9 min of hypoxia and hypoglycemia (ischemia). The noncompetitive NMDA antagonist MK-801 produced significant protection of the slices, whereas the competitive NMDA antagonist D-CPP did not. Administration of the strychnine-insensitive glycine-modulatory site antagonists (ACEA 1021, GV150,526A, and L701,324) up to 10 mu M did not result in significant recovery of function. Other animal models have suggested that glycine antagonists are beneficial 6-48 hours after ischemic insult; this model assayed functional recovery for only 1 hour after the insult. Therefore, we conclude that this acute in vitro electrophysiologic model may not be useful in detecting the potential neuroprotective properties of glycine antagonists. (C) 1999 Wiley-Liss, Inc.