Abstract

Rats were made tolerant to the hypnotic effects of thealpha-2 adrenergic agonist dexmedetomidine by a 7- or 14-day continuous systemic administration of the same, and the ability of nifedipine to reverse dexmedetomidine tolerance was assessed. Acute administration of nifedipine (10 mg/kg i.p.) restored the hypnotic response to dexmedetomidine in the alpha-2 tolerant rats. Concurrent administration of nifedipine during induction of tolerance, either partially (continuous administration 10 mg/kg/day delivered by minipumps) or completely (twice daily injections, 20 mg/kg s.c.) restored hypnotic responsiveness to control levels. Induction of tolerance reduced the affinity of [³H]PN200–110 for the L-type calcium channel. Chronically administered nifedipine treatment (20 mg/kg s.c. twice daily), at doses that partially restored the behavioral response to normal, did not change ligand binding affinity of [³H]PN200–110. An increase inB_max for [³H]PN200–110 was noted in the dexmedetomidine tolerant state which did not change with chronic nifedipine. In naive rats, the phosphodiesterase inhibitor rolipram (275 μg/kg i.p.), mimicked the state of tolerance, as it resulted in a decreased hypnotic response to dexmedetomidine. Nifedipine (10 mg/kg i.p.) also reversed the rolipram-induced attenuation of the hypnotic response to dexmedetomidine. These data implicate a role for the L-type calcium channel in the mechanism of the hypnotic response in alpha-2 tolerant rats and suggest the involvement of the cAMP pathway.