D-CYCLOSERINE, A PARTIAL AGONIST AT THE GLYCINE SITE, ENHANCES THE EXCITABILITY OF DENTATE GRANULE CELLS IN-VIVO IN RATS

The present study investigated the dose-dependent effects of d-cycloserine, a partial agonist at the glycine modulatory site associated with the NMDA receptor complex. on the hippocampal field potentials of dentate granule cells in awake, freely moving rats. Five sequential field potentials were recorded from the dentate gyrus of the dorsal hippocampus, by stimulating the perforant path in the entorhinal cortex at 30-s intervals. The slope of the population excitatory postsynaptic potential (e.p.s.p.) and the amplitude of the population spike of these field potentials were analysed and averaged with a computer. The effects of d-cycloserine (1.0, 3.0, 9.0 mg/kg) were recorded 40 min and 24 h after the i.p. injection. Although the slope of the population e.p.s.p. showed no significant change after the administration of d-cycloserine, the high doses produced a substantial increase in the amplitude of the population spike. This increase was observed 40 min but not 24 h after the injection. These findings indicate that d-cycloserine does not change the synaptic input from the perforant path to the granule cells but dose dependently enhances the excitability of the hippocampal dentate granule cells. In addition, the data give further support to the suggestion that in the brain area where NMDA receptor density is relatively high, the glycine site of the NMDA receptor may not be fully saturated by endogenous glycine in normal in vivo conditions. This suggests that there is a possibility for pharmacological modulation of NMDA receptor-mediated synaptic events by exogenous glycine or glycine analogues.