Glycine(B) receptor antagonists and partial agonists prevent memory deficits in inhibitory avoidance learning

Activation of N-methyl-D-aspartate (NMDA) receptors has been hypothesized t o mediate certain forms of learning and memory. This hypothesis is based on the ability of competitive and uncompetitive NMDA receptor antagonists to disrupt learning. We investigated the effects of glycine site antagonists a nd partial agonists on deficits of acquisition (learning) and consolidation (memory) in a single trial inhibitory avoidance learning paradigm. Posttra ining administration of either hypoxia (exposure to 7% oxygen) or the convu lsant drug pentylenetetrazole (PTZ) (45 mg/kg) to mice impaired consolidati on without producing neuronal cell death. Pretreatment with the competitive glycine antagonist 7-chlorokynurenic acid (7KYN) and the glycine partial a gonists 1-aminocyclopropanecarboxylic acid (ACPC) and (+)HA-966 prevented m emory deficits induced by hypoxia and PTZ, but did not affect scopolamine-i nduced learning impairment. In addition, ACPC prevented consolidation defic its evoked by a nonexcitotoxic concentration of L-trans-pyrrolidine-2, 4-di carboxylate, a competitive inhibitor of glutamate transport that increases extracellular levels of glutamate. Moreover, (+)HA-9GG, 7KYN, and ACPC faci litated both acquisition and consolidation of inhibitory avoidance training , an effect that was dose-dependent and reversed by glycine. These results indicate that memory deficits induced by both hypoxia and PTZ involve NMDA receptor activation. Furthermore, the present findings demonstrate that gly cine site antagonists and partial agonists prevent memory deficits of inhib itory avoidance learning by affecting consolidation, but not acquisition pr ocesses. (C) 2000 Academic Press.