Abstracts

Rationale: Zolpidem is a hypnotic medication that mainly exerts its function through activating ?-aminobutyric acid (GABA)A receptors. There is some evidence that zolpidem may have anticonvulsant effects. However, the mechanisms underlying this effect has not been elucidated yet. In the present study, we used the pentylentetrazol (PTZ)-induced generalized seizure model in mice to investigate whether zolpidem can affect seizure threshold. We also further evaluated the role of ATP-sensitive potassium (KATP) channels as well as -opioid receptors in the effects of zolpidem on seizure threshold. Methods: Male NMRI mice weighing 20?"25 g (Pasteur Institute) were used throughout this study. Determination of clonic seizure threshold PTZ-induced clonic seizure threshold was determined by inserting a 30-gauge butterfly needle into the tail vein of mice and the infusion of PTZ (0.5%) at a constant rate of 1 ml/min to unrestrained freely moving animals. Infusion was halted when forelimb clonus followed by full clonus of the body was observed. Minimal dose of PTZ (mg/kg of mice weight) needed to induce clonic seizure was considered as an index of seizure threshold. Zolpidem or its vehicle was injected intraperitoneally (i.p.) 30 minutes prior PTZ-induced seizure. The KATP channel or opioid modulators and their vehicles were injected (i.p.) 30 minutes prior zolpidem injection or 60 minutes prior PTZ injection. Data are expressed as mean S.E.M. of clonic seizure threshold in each experimental group. The one-way or two-way analysis of variance (ANOVA) followed by Newman?"Keuls post hoc test was used to analyze the data. In all experiments, a P value less than 0.05 was considered statistically significant. Results: Zolpidem in a dose dependent manner (1, 3, and 10 mg/kg) increased the PTZ-induced seizure threshold (P < 0.001). The non-effective doses of KATP channel blocker (glibenclamide, 0.1 and 1 mg/kg) and -opioid receptor antagonist (naloxone, 0.1 and 1 mg/kg) inhibited this effect of zolpidem (P < 0.01 and P < 0.001). Additionally, non-effective doses of either KATP channel opener (cromakalim, 10 g/kg) or -opioid receptor agonist (morphine, 1 mg/kg) in combined with non-effective dose of zolpidem (1 mg/kg) exerted a significant anticonvulsant effect on pentylenetetrazol (PTZ)-induced seizures in mice (P < 0.001). Combination of non-effective doses of naloxone (0.03 mg/kg) and glibenclamide (0.03 mg/kg), that separately did not affects zolpidem (10 mg/kg) effect on seizure threshold, inhibited the anticonvulsant effects of zolpidem (P < 0.01). Conclusions: These results suggest a role for KATP channels and opioid system, alone or in combination, in the anticonvulsant effects of zolpidem. Funding: The present study was funded by the grant from Tehran University of Medical Sciences.