Psychomotor stimulant effects of methylxanthines in squirrel monkeys: relation to adenosine antagonism

Abstract

The behavioral effects of six methylxanthines were studied in squirrel monkeys responding under a fixed-interval (FI) schedule of stimulus-shock termination. Dose-response curves were determined for each drug by administering cumulative doses IV during timeout periods that preceded sequential components of the FI schedule. Low to intermediate doses of caffeine, theophylline, 8-phenyltheophylline (8-PT), 8-cyclopentyltheophylline (CPT), and 3-isobutyl-1-methylxanthine (IBMX) produced dose-related increases in response rate, whereas higher doses increased response rate less or decreased it. Enprofylline did not increase response rate at any dose. Pretreatment with a high dose of the adenosine agonist 5'-N-ethylcarboxamide adenosine (NECA) suppressed responding throughout the experimental session. Caffeine, theophylline, 8-PT, CPT, and IBMX, but not enprofylline, antagonized the suppressant effects of NECA in a dose-related manner. The potencies of the methylxanthines for increasing response rate under the FI schedule were positively correlated with their potencies for antagonizing the suppressant effects of NECA, suggesting that the psychomotor stimulant effects of methylxanthines are linked to their antagonistic actions at adenosine recognition sites. CPT, which in vitro has much higher affinity (greater than 10(3)-fold) than caffeine for adenosine A1, but not for A2, recognition sites, was only 3-6 times more potent than caffeine in increasing response rate or in antagonizing the effects of NECA. The psychomotor stimulant effects of methylxanthines therefore appear to be more closely associated with antagonism at adenosine A2 than adenosine A1 recognition sites.