PT  - JOURNAL ARTICLE
AU  - Leonard L. Howell
AU  - Alyson M. Landrum
TI  - Effects of Chronic Caffeine Administration on Respiration and Schedule-Controlled Behavior in Rhesus Monkeys
DP  - 1997 Oct 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 190--199
VI  - 283
IP  - 1
4099  - http://jpet.aspetjournals.org/content/283/1/190.short
4100  - http://jpet.aspetjournals.org/content/283/1/190.full
SO  - J Pharmacol Exp Ther1997 Oct 01; 283
AB  - 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. The American Society for Pharmacology and Experimental Therapeutics