Effects of CGS 15943, a nonxanthine adenosine antagonist, on behavior in the squirrel monkey

The behavioral effects of CGS 15943 (0.1-3.0 mg/kg), a nonxanthine adenosine antagonist lacking phosphodiesterase (PDE) inhibitory effects, and caffeine (1.0-30.0 mg/kg), a xanthine adenosine antagonist with PDE inhibitory effects, were compared in squirrel monkeys trained to lever-press under fixed interval (FI) schedules of food presentation or stimulus termination. Both adenosine antagonists increased FI response rates after i.m. or i.v. administration, with CGS 15943 being more efficacious and approximately 3 to 10 times more potent than caffeine. Moreover, the rate-increasing effects of caffeine were enhanced by CGS 15943 (0.3 and 1.0 mg/kg) pretreatment. In contrast, rolipram (0.01-0.1 mg/kg), a potent PDE inhibitor lacking adenosine-antagonist effects, only decreased response rates. The nonselective adenosine agonist, 5'-N-ethylcarboxamidadenosine (0.003-0.03 mg/kg), the A1-selective adenosine agonists, N6-cyclopentyladenosine (0.1-1.0 mg/kg) and N6-cyclohexyladenosine (0.1-1.0 mg/kg) and the A2-selective adenosine agonist, CGS 21680 (0.03-0.3 mg/kg), produced dose-dependent decreases in response rates that were attenuated by CGS 15943 and caffeine. The potency difference between CGS 15943 and caffeine as antagonists of 5'-N-ethylcarboxamidadenosine, N6-cyclopentyladenosine and N6-cyclohexyladenosine corresponded to the potency difference of the two drugs for increasing FI response rates. In contrast, CGS 15943 and caffeine were approximately equipotent as antagonists of CGS 21680. The similarity of the effects of CGS 15943 and caffeine supports and extends previous findings suggesting that the behavioral-stimulant effects of caffeine and other xanthines are mediated through adenosine-antagonist actions rather than inhibition of PDE activity.