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 antag onist 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 susceptibilit y to the adverse effects of competitive and non-competitive NMDA recep tor antagonists. Since (+)-HA-966 displays weak partial agonistic effe cts at the glycine site (similar to 10% efficacy of glycine), D-cyclos erine, a glycine ligand with much higher intrinsic activity, was evalu ated in kindled rats for comparison. Following drug administration, el ectrographic activity was recorded from the basolateral amygdala (i.e. the focal site) as well as the ipsilateral piriform cortex, ventral h ippocampus and nucleus accumbens. In addition to the evaluation of ori ginal recordings, power spectrum analysis was used to delineate drug e ffects. (+)-HA-966 (20-40 mg/kg i.p.) induced marked alterations in el ectrographic 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 seizu re activity following a kindled motor seizure. In contrast to (+)-HA-9 66, D-cycloserine did not induce any electrographic changes, even when administered in much higher doses than (+)-HA-966. The changes in ele ctrographic recordings seen after administration of (+)-HA-966 in kind led rats were almost absent in non-kindled rats, indicating that kindl ing had increased the sensitivity to the paroxysmal effects of the gly cine/NMDA receptor ligand. The data indicate that functional glycine/N MDA antagonists with low intrinsic efficacy may bear the risk of proco nvulsant activity.