The present study was undertaken to investigate the effect of diltiazem, a L-type calcium channel blocker (CCB), on the behavior of zolpidem-treated mice in the elevated plus-maze (EPM). Atypical benzodiazepine zolpidem significantly increased the percentage of open arm entries without influencing the total entries and total distance and average speed at the dose of 5 mg/kg (p.o.). Co-administration of zolpidem (2 mg/kg, p.o.) and diltiazem (5, 10 and 20 mg/kg, p.o.) significantly increased both the time spent and arm entries in the open arms without influencing the total entries and spontaneous activity notwithstanding that zolpidem at dose up to 2 mg/kg (p.o.) and diltiazem at dose up to 20 mg/kg (p.o.) did not show any effects on mice behavior in EPM. Zolpidem also attenuated the anxiogenic effect of 1-(3-Chlorophenyl)piperazine (mCPP, 0.7 mg/kg, i.p.) and 5-hydroxytryptophan (5-HTP, 30 mg/kg, i.p.). Even though the zolpidem at 1 mg/kg and diltiazem at 5 mg/kg were ineffective on mCPP-induced anxiety, respectively, the co-administration of zolpidem (1 mg/kg, i.p.) and diltiazem (5 mg/kg, p.o.) showed inhibitory effect on mCPP-induced anxiety in mice. These results suggested that diltiazem, a L-type CCB may augment the anxiolytic-like effect of zolpidem and also indicated that calcium channel modulation maybe involved in the anxiolytic-like properties of zolpidem.
In order to elucidate the mechanism(s) behind the interactions between barbiturates and Ca(2+) antagonists, the effects of three structurally diverse types of Ca(2+) antagonists combined or not with 5-HT on pentobarbital-induced hypnosis in mice were investigated. The results showed that dihydropyridine derivative nifedipine (10.0 and 20.0 mg/kg, p.o.) and other types of Ca(2+) antagonist, verapamil (5.0 and 10.0 mg/kg, p.o.) and diltiazem (2.5, 5.0 and 10.0 mg/kg, p.o.) increased both the sleeping time in hypnotic dosage of pentobarbital (45 mg/kg, i.p.) treated mice and the rate of sleep onset in the sub-hypnotic dosage of pentobarbital (28 mg/kg, i.p.) treated mice in a dose-dependent manner, respectively, and these effects were significantly augmented by 5-hydroxytryptophan (5-HTP), the immediate precursor of 5-hydroxytryptamine (5-HT). Pretreatment with p-chlorophenylalanine (PCPA, 300 mg/kg, s.c.), an inhibitor of tryptophan hydroxylase, significantly decreased pentobarbital-induced sleeping time and nifedipine (10.0 mg/kg, p.o.), verapamil (5.0 mg/kg, p.o.) and diltiazem (2.5 mg/kg, p.o.) abolished this effect. From these results, it should be presumed that the augmentative effect of L-type Ca(2+) channel blockers on pentobarbital-induced sleep may be influenced by serotonergic system.
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