Low doses of the glycine/NMDA receptor antagonist R-(+)-HA-966 but not D-cycloserine induce paroxysmal activity in limbic brain regions of kindled rats.

(+)-HA-966 [R-(+)-3-amino-1-hydroxypyrrolid-2-one], a functional antagonist at the glycine modulatory site on the N-methyl-D-aspartate (NMDA) receptor/ion channel complex, was evaluated in amygdala-kindled rats, a model of epilepsy recently shown to exhibit enhanced susceptibility to the adverse effects of competitive and non-competitive NMDA receptor antagonists. Since (+)-HA-966 displays weak partial agonistic effects at the glycine site (approximately 10% efficacy of glycine), D-cycloserine, a glycine ligand with much higher intrinsic activity, was evaluated in kindled rats for comparison. Following drug administration, electrographic activity was recorded from the basolateral amygdala (i.e. the focal site) as well as the ipsilateral piriform cortex, ventral hippocampus and nucleus accumbens. In addition to the evaluation of original recordings, power spectrum analysis was used to delineate drug effects. (+)-HA-966 (20-40 mg/kg i.p.) induced marked alterations in electrographic recordings, including increases in amplitude and isolated spiking, i.e. signs of paroxysmal activity. The severity or duration of fully kindled seizures was not changed by (+)-HA-966, but the drug dramatically increased the duration of immobilization and limbic seizure activity following a kindled motor seizure. In contrast to (+)-HA-966, D-cycloserine did not induce any electrographic changes, even when administered in much higher doses than (+)-HA-966. The changes in electrographic recordings seen after administration of (+)-HA-966 in kindled rats were almost absent in non-kindled rats, indicating that kindling had increased the sensitivity to the paroxysmal effects of the glycine/NMDA receptor ligand. The data indicate that functional glycine/NMDA antagonists with low intrinsic efficacy may bear the risk of proconvulsant activity.