NMDA receptor antagonists protect against seizures and wet-dog shakes induced by 4-aminopyridine.

The effect of N-methyl-D-aspartate (NMDA) and non-NMDA receptor antagonists on the generalized tonic-clonic convulsions and wet-dog shakes induced by the intraperitoneal (i.p.) or the intrahippocampal (i.h., stereotaxic microinjection into the CA1 region) administration of 4-aminopyridine (4-AP) was studied in rats. Pretreatment with NMDA competitive and non-competitive antagonists resulted in potent protection against the motor effects of both the i.p. and the i.h. administration of 4-AP. MK-801 (0.25 mg/kg i.p.) and 3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP, 0.8 nmol intracerebroventricular, i.c.v.) showed the most powerful anticonvulsive effect, since they prevented the occurrence of generalized tonic convulsions and the death of the animals in convulsions after i.p. 4-AP. The i.c.v. injection (10 nmol) of the NMDA competitive antagonists 2-amino-5-phosphonopentanoate (AP-5) and 2-amino-5-phosphonoheptanoate (AP-7) also showed a clear though less potent protective effect. Similarly, the frequency of wet-dog shakes induced by i.h. 4-AP was markedly decreased by pretreating the animals with i.p. MK-801 or with i.c.v. CPP or AP-7. However, the co-injection of CPP with 4-AP failed to protect against the occurrence of wet-dog shakes. The i.c.v. pretreatment with the unselective antagonist, kynurenate (up to 68 nmol) or with the non-NMDA receptor antagonist, 6-cyano-7-nitroquinoxaline-2,3-dione (0.5 nmol), did not significantly modify the effects of 4-AP when administered either i.p. or i.h. We conclude that NMDA receptors are involved in the mechanism of the convulsive activity induced by 4-AP, probably because this drug induces the release of glutamate.

Seizures and wet-dog shakes induced by 4-aminopyridine, and their potentiation by nifedipine.

The behavioral and electrographic effects of 4-aminopyridine (4-AP) administered i.p. or microinjected into the hippocampal CA1 region (i.h.) were studied in rats. The modification of such effects by the systemic administration of the Ca2+ antagonist dihydropyridine, nifedipine, was also studied. 4-AP i.p. (5 mg/kg) induced generalized tonic convulsions in 74% of the animals and death in 13%. Convulsions were characterized by electrical discharges of relatively short duration in all structures studied (frontal cortex, amygdala, dorsal hippocampus and dorsal raphe). Limbic seizures and frequent wet-dog shakes were observed when 4-AP was administered i.h. (2-4 nmol) and this behavior was correlated with hippocampal discharges, which rapidly propagated to the other structures. Pretreatment with nifedipine (7.5-50 mg/kg s.c.) markedly potentiated the effects of 4-AP. The percentage of rats that died during generalized convulsion after i.p. 4-AP increased to 56-87% and the frequency of wet-dog shakes increased after i.h. microinjection of 4-AP. Moreover, nifedipine-treated rats showed long-lasting (greater than 60 min) continuous discharges in all structures studied (status epilepticus). These results are discussed in the light of the possible participation of Ca2+ channels in the convulsant effect of 4-AP and its potentiation by nifedipine.