Lindane-induced convulsions in NMRI and OF1 mice: antagonism with (+) MK-801 and voltage-dependent calcium channel blockers

Abstract

The convulsant profile of lindane was investigated in OF1 and NMRI mice lines in relation to other convulsants acting at the GABA A and NMDA receptor complexes. Thus, a specific GABA-gated chloride channel blocker, PTX, a GABA A receptor antagonist, PTZ, and an excitatory amino acid receptor agonist, NMDA, were used. Antagonism of the convulsant effects of each of these drugs was investigated with (+)MK-801, a blocker of the NMDA-operated cation channel, and with nifedipine, a voltage-dependent calcium channel antagonist. While no differences in potency for PTX or PTZ to induce seizures were observed between OF1 and NMRI mice. lindane was approximately 80 and 90% more polent in its ability to induce seizures and lethality, respectively, in OF1 than NMRI mice. Brain lindane concentrations at the moment of convulsion, measured after ED 100 doses of lindane (400 and 200 mg/kg for NMRI and OF1 mice, respectively), did not differ between OF1 and NMRI mice, suggesting that the different potency of lindane between these mouse lines is a consequence of pharmacokinetic factors. Furthermore, (+)MK-801 antagonized seizures induced by either lindane, PTX or PTZ with similar potencies in both mouse lines. These results, coupled with the different pharmacokinetics of lindane in OF1 and NMRI mice, suggest that the distinct effects of lindane in these mice are not mediated by different activities at either NMDA or GABA A receptor complexes. Nonetheless, nifedipine antagonized lindane-induced seizures with a three-fold higher potency in NMRI than in OF1 mice. In contrast, nifedipine failed to antagonize PTX and PTZ convulsions in both OFI and NMRI mice. These results suggest that besides the GABA A receptor complex other mechanisms related to calcium mobilization may be involved in the convulsant action of lindane.