Effects of the novel NMDA antagonist, NPC 12626, on long-term potentiation, learning and memory.

NPC 12626 (2-amino-4,5-(1,2-cyclohexyl)-7-phosphonoheptanoic acid), a newly developed drug which crosses the blood-brain barrier, is a competitive antagonist of N-methyl-D-aspartate receptors. In Experiment I, the effects of NPC 12626 on perforant path - dentate gyrus LTP were tested. NPC 12626 (100 mg/kg, i.p.), injected 150 min prior to tetanization, prevented potentiation of the EPSP slope and population spike amplitude. EPSP-spike potentiation was also prevented. Post-tetanus administration was ineffective. In Experiment II, mice were injected with NPC 12626 (35 mg/kg, i.p.) or saline 35 min prior to spontaneous alternation testing. NPC 12626 significantly decreased alternation rates, but did not affect turn bias or the mean delay between arm entries. This pattern of results may reflect impaired learning or memory. In Experiment III, mice were tested on an inhibitory avoidance task. NPC 12626 (35 mg/kg, i.p.), administered before but not after training, significantly impaired performance. When the drug was administered before training as well as before testing, performance was similarly impaired, indicating that the observed deficits were not attributable to state-dependent learning. Pre-test injections were ineffective. Overall, these results support the hypothesis that some forms of learning require the participation of NMDA receptors and that this participation is largely limited to acquisition processes. In addition, these results point to the utility of peripherally administered NPC 12626 as a tool with which to examine the involvement of NMDA receptors in LTP and learning.