(+)-
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.