NIFEDIPINE, AN L-TYPE CALCIUM-CHANNEL BLOCKER, RESTORES THE HYPNOTIC RESPONSE IN RATS MADE TOLERANT TO THE ALPHA-2-ADRENERGIC AGONIST DEXMEDETOMIDINE

Rats were made tolerant to the hypnotic effects of the alpha-2 adrener gic agonist dexmedetomidine by a 7- or 14-day continuous systemic admi nistration of the same, and the ability of nifedipine to reverse dexme detomidine tolerance was assessed, Acute administration of nifedipine (10 mg/kg i.p.) restored the hypnotic response to dexmedetomidine in t he alpha-2 tolerant rats. Concurrent administration of nifedipine duri ng induction of tolerance, either partially (continuous administration 10 mg/kg/day delivered by minipumps) or completely (twice daily injec tions, 20 mg/kg s.c.) restored hypnotic responsiveness to control leve ls, Induction of tolerance reduced the affinity of [H-3]PN200-110 for the L-type calcium channel. Chronically administered nifedipine treatm ent (20 mg/kg s.c. twice daily), at doses that partially restored the behavioral response to normal, did not change ligand binding affinity of [H-3]PN200-110. An increase in B-max for [H-3]PN200-110 was noted i n the dexmedetomidine tolerant state which did not change with chronic nifedipine, In naive rats,the phosphodiesterase inhibitor rolipram (2 75 mu g/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 r esponse 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.