EFFECTS OF CGS-15943, A NONXANTHINE ADENOSINE ANTAGONIST, ON BEHAVIORIN THE SQUIRREL-MONKEY

The behavioral effects of CGS 15943 (0.1-3.0 mg/kg), a non-xanthine ad enosine antagonist lacking phosphodiesterase (PDE) inhibitory effects, and caffeine (1.0-30.0 mg/kg), a xanthine adenosine antagonist with P DE inhibitory effects, were compared in squirrel monkeys trained to le ver-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 ef ficacious and approximately 3 to 10 times more potent than caffeine. M oreover, 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 adeno sine agonists, N6-cyclopentyladenosine (0.1-1.0 mg/kg) and N6-cyclohex yladenosine (0.1-1.0 mg/kg) and the A2-selective adenosine agonist, CG S 21680 (0.03-0.3 mg/kg), produced dependent decreases in response rat es that were attenuated by CGS 15943 and caffeine. The potency differe nce between CGS 15943 and caffeine as antagonists of 5'-N-ethylcarboxa midadenosine, N6-cyclopentyladenosine and N6-cyclohexyladenosine corre sponded to the potency difference of the two drugs for increasing FI r esponse 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 sugge sting that the behavioral-stimulant effects of caffeine and other xant hines are mediated through adenosine-antagonist actions rather than in hibition of PDE activity.