BEHAVIORAL AND PHYSIOLOGICAL-EFFECTS OF XANTHINES IN NONHUMAN-PRIMATES

Caffeine and related xanthines can have significant behavioral effects on measures of locomotor activity, schedule-controlled behavior, drug self-administration, and learning and memory. Xanthines also produce numerous physiological effects including positive inotropic and chrono tropic effects on the heart, decreased airway resistance in the lung, and respiratory stimulation. Due to the widespread use of xanthines as constituents of food and beverages and as therapeutic drugs, identifi cation of mechanisms that mediate their pharmacological effects has co nsiderable relevance for drug development and therapeutics. Two primar y mechanisms involving the cyclic nucleotide system have been implicat ed as the bases for the effects of xanthines in the CNS. Many xanthine s bind to specific adenosine recognition sites and block the actions o f adenosine. Xanthines also inhibit cyclic nucleotide phosphodiesteras es, the enzymes responsible for the hydrolytic inactivation of cyclic AMP and cyclic GMP. Recent research in nonhuman primates has character ized the behavioral, respiratory and cardiovascular effects of a numbe r of xanthines and related drugs differing in affinity at different su btypes of adenosine receptors and in capacity to inhibit different mol ecular forms of PDE. The behavioral-stimulant effects of xanthines app ear to be mediated principally by their adenosine-antagonist actions a nd may be limited by PDE inhibition. The respiratory-stimulant and car diac effects of xanthines, on the other hand, appear to be linked more closely to their PDE-inhibiting actions than to adenosine antagonism. Converging lines of evidence suggest that adenosine A(2) and cAMP-spe cific (possibly type IV) PDE mechanisms play especially prominent role s in mediating the behavioral and physiological effects of xanthines i n nonhuman primates.