WEAK ANTICONVULSANT EFFECTS OF 2 NOVEL GLYCINE(B) RECEPTOR ANTAGONISTS IN THE AMYGDALA-KINDLING MODEL IN RATS

In the present work we evaluated the anticonvulsant effects of two nov el antagonists of the glycine co-agonist site (glycine(B) receptor) wi thin the N-methyl-D-aspartate (NMDA) receptor complex, MRZ 2/576 (a tr icyclic pyrido-phtalazin dione derivative) and L-701,324 hloro-4-hydro xy-3-(3-phenoxy)phenyl-(H)quinoline). As a model of epilepsy we used a mygdala-kindled rats, which are considered as a model to study the eff icacy of drugs against human complex partial seizures. MRZ 2/576 (2.5- 10 mg/kg i.p. 15 min before testing) did not influence afterdischarge threshold, which is believed to be the most subtle indicator of effica cy against kindled seizures, nor did it affect other measures of seizu re activity such as seizure severity, seizure duration and afterdischa rge duration. However, MRZ 2/576 produced dose-dependent ataxia as mea sured in the open field and rotarod test. The highest dose tested (10 mg/kg) also markedly reduced rectal temperature (by about 1.5 degrees C). L-701,324 (2.5-10 mg/kg i.p. 30 min before testing) dose dependent ly and significantly increased afterdischarge threshold, but other sei zure parameters remained unchanged. The ataxia produced by lower doses of L-701,324 (2.5 and 5 mg/kg) was mon pronounced than that caused by MRZ 2/576. However, the ataxia observed following the higher dose of L-701,324 (10 mg/kg) was less intense than that elicited by MRZ 2/576. The behavioral alterations produced by the two drugs did not resemble those characteristic for classical competitive and uncompetitive NMDA receptor antagonists. In conclusion, our data indicate that glycine, receptor antagonists are not promising candidates for the treatment of complex partial seizures in humans, at least as monotherapy. (C) 1998 Elsevier Science B.V.