Caffeine and related xanthines are behaviorally-active drugs used clinically as respiratory stimulants, but biochemical mechanisms that mediate the behavioral and respiratory effects remain undefined. Studies have implicated both antagonism of adenosine receptors and inhibition of phosphodiesterase activity as possible mechanisms that mediate their central effects. Because of the widespread use of xanthines as therapeutic drugs and as constituents of food and beverages, studies are proposed to (1) investigate mechanisms that mediate the behavioral and respiratory- stimulant effects of xanthines, (2) establish a nonhuman primate model of caffeine tolerance, (3) characterize the interactions of caffeine and nicotine during acute and chronic administration of both drugs, and (4) compare the effects of caffeine to those of cocaine to assess the pharmacological specificity of drug effects and to provide critical information regarding the behavioral and respiratory effects of cocaine. Ventilation (minute volume, tidal volume and respiratory frequency) in unanesthetized rhesus monkeys will be monitored continuously with a pressure-displacement, head plethysmograph while a medical gas analyzer monitors carbon dioxide and oxygen tensions in expired air. Drug effects on ventilation will be determined during exposure to normal atmospheric conditions and during conditions of hypercapnia, hypoxia and hyperoxia. Operant behavior will be studied while ventilation is being monitored to provide direct comparisons of drug effects on behavior and on respiration. Additionally, the pharmacokinetics of caffeine and cocaine will be determined by high-performance liquid chromatography analysis. A wide range of doses of caffeine and related drugs with selective actions as adenosine-receptor agonists and antagonists and as phosphodiesterase inhibitors will be determined in caffeine-tolerant and non-tolerant animals. Altered pharmacokinetics and sensitivity to caffeine and related stimulants during chronic drug administration, in conjunction with acute drug interactions, will have important implications for the study of drug abuse and for the establishment of appropriate drug-abuse policy.
