A PEPTIDASE-RESISTANT CYCLIC OCTAPEPTIDE ANALOG OF SOMATOSTATIN (SMS-201-995) MODULATES SEIZURES INDUCED BY QUINOLINIC AND KAINIC ACIDS DIFFERENTLY IN THE RAT HIPPOCAMPUS

Electroencephalographic (EEG) seizures were measured in rats after intrahippocampal injection of 120 nmol quinolinic acid into the stratum radiatum CA1 or 0.19 nmol kainic acid in the dentate gyrus or in the stratum radiatum. Injection of 5-mu-g SMS 201-995, a peptidase-resistant cyclic octapeptide analogue of somatostatin, into the stratum radiatum, 15 min before quinolinic acid, did not significantly modify the number of seizures and the total time in seizures. Five mu-g SMS 201-995 injected into the stratum radiatum reduced the number of seizures induced by kainic acid in the same area and the total time spent in seizures by 58% and 75%, respectively (Student's t-test; P < 0.01). In both instances the latency to the first ictal episode was not significantly modified. Lesions of the medial septum, which reduced the activity of choline-o-acetyl-transferase (CAT) in the dorsal hippocampus by > 90% after one week did not significantly affect seizures induced by quinolinic acid. In rats lesioned in the medial septum, 5-mu-g SMS 201-995 reduced the total time spent in seizures by 43%, without changing the number of ictal episodes and raised the latency to the first quinolinic acid-induced seizure by 53% (ANOVA 2 x 2, P < 0.05) but had no effect on these measures in the corresponding sham-operated group. A significant, 50% reduction of the total time spent in seizures and a 20% increase in the latency to the first quinolinic acid-induced seizure, with no changes in the number of ictal episodes, were observed when 5-mu-g SMS 201-995 was injected intrahippocampally with 10-mu-g atropine (ANOVA 2 x 2, P < 0.05), a muscarinic receptor antagonist, which per se did not significantly change seizures caused by quinolinic acid. Five mu-g of the peptide into the dentate gyrus reduced the total time spent in seizures induced by kainic acid, in the same area by about 60% and significantly reduced the number of seizures by 33% (Dunnett's test; P < 0.05). Picrotoxin (2 mg/kg, i.p. or 1.5 nmol into the dentate gyrus), a GABA(A) receptor antagonist, did not alter the EEG pattern induced by kainic acid in the gyrus or modify the anticonvulsant effect of SMS 201-995 on seizures induced by kainic acid.