Abstract
The effects of chronic caffeine administration on ventilation and schedule-controlled behavior were studied in 12 adult rhesus monkeys. In seated subjects prepared with a head plethysmograph, ventilation was measured during exposure to air (normocapnia) and to elevated levels of CO2 (3%, 4% and 5%) mixed in air (hypercapnia). Acute administration of caffeine (10.0–30.0 mg/kg i.m.) produced marked, dose-dependent increases in ventilation during conditions of normocapnia and hypercapnia. However, daily administration of caffeine (10.0 mg/kg i.m.) for 8 consecutive days resulted in tolerance to its respiratory-stimulant effects that was surmountable with higher doses. Caffeine-tolerant subjects also were cross-tolerant to theophylline, an active metabolite of caffeine, and to rolipram and Ro 20–1724, selective phosphodiesterase inhibitors. When chronic administration was terminated and the acute effects of caffeine were redetermined, sensitivity returned to levels obtained before chronic administration within 9 days. Drug effects on behavior were studied in monkeys trained to respond under a fixed-interval schedule of stimulus termination. Acute administration of caffeine (1.0–30.0 mg/kg i.m.) produced significant rate-increasing effects on fixed-interval responding, but chronic administration resulted in tolerance that was insurmountable, such that no dose increased responding above control rates. Although the time course for development and loss of tolerance to the behavioral effects of caffeine corresponded closely with respiration, cross-tolerance did not extend to the behavioral effects of rolipram. Chronic caffeine administration had little effect on caffeine metabolism or clearance, which indicated that caffeine tolerance was pharmacodynamic. The results suggest that different neurochemical mechanisms mediate the effects of caffeine on respiration and behavior, and that inhibition of type IV phosphodiesterase plays a prominent role in caffeine-induced respiratory stimulation.
Footnotes
-
Send reprint requests to: Dr. Leonard L. Howell, Yerkes Regional Primate Research Center, Emory University, Atlanta, GA 30322.
-
↵1 This research was supported, in part, by U.S. Public Health Service grants DA-05346, DA-01161, DA-06264 and RR-00165 (Division of Research Resources, National Institutes of Health). The Yerkes Primate Research Center is fully accredited by the American Association for Accreditation of Laboratory Animal Care.
- Abbreviations:
- VE
- minute volume
- VT
- tidal volume
- f
- respiratory frequency
- FI
- fixed interval
- PDE
- phosphodiesterase
- cAMP
- cyclic AMP
- CNS
- central nervous system
- HPLC
- high-performance liquid chromatography
- Received January 14, 1997.
- Accepted June 9, 1997.
- The American Society for Pharmacology and Experimental Therapeutics
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|