Amelioration of caffeine-induced seizures by modulators of sigma, N-methyl-d-Aspartate and ryanodine receptors in mice

Objectives The aim of this study was to evaluate the antiepileptic effects of opipramol, a sigma receptor agonist, diazepam, ketamine, an N-methyl-d-Aspartate (NMDA) receptor antagonist, and dantrolene, a ryanodine receptor antagonist, against caffeine-induced seizures in mice.Methods We used caffeine (1000 mg/kg) intraperitoneally for inducing clonic and tonic-clonic seizures in male albino Swiss strain of mice. We used opipramol in three different doses (10, 20 and 50 mg/kg), ketamine (50 mg/kg), dantrolene (40 mg/kg), opipramol (20 mg/kg) plus ketamine (50 mg/kg), opipramol (20 mg/kg) plus dantrolene (40 mg/kg), diazepam (5 mg/kg as a positive control) and the vehicle 30 min before injecting caffeine. We recorded the onset of clonic, tonic-clonic seizures and the time of death of animals after using caffeine.Results Animals treated with opipramol at a dose of 50 mg/kg or diazepam had a higher onset of clonic seizure compared with the vehicle-treated group. Dantrolene alone or with opipramol (20 mg/kg) increased the latency of clonic seizure compared with the control group. Opipramol (20 and 50 mg/kg), diazepam, ketamine alone or with opipramol, and dantrolene plus opipramol increased the latency of tonic-clonic seizures in mice. All the treatments except opipramol (10 mg/kg) and dantrolene alone increased the latency of death of animals.Conclusion Opipramol attenuated seizures produced by high doses of caffeine. Moreover, the activation of sigma receptors and inhibition of ryanodine receptors may produce synergistic effects against caffeine-induced seizures. Our study may imply that different mechanisms such as inhibition of gamma-aminobutyric acid-A receptors, activation of NMDA and ryanodine receptors may contribute to the caffeine-induced seizures.