Rats treated chronically with caffeine become tolerant to caffeine-induced stimulation of locomotor activity and cross-tolerant to theophylline. This study was performed to determine if the cross-tolerance between these two methylxanthine drugs is symmetrical. Symmetrical cross-tolerance produced by two different drugs implies a common underlying mechanism of action. Separate groups of rats were given scheduled access to drinking bottles containing either drug-free tap water or 1.0 mg/ml theophylline solution. Daily theophylline intake averaged 59 mg/kg. Dose-effect curves were determined in both control and theophylline-treated groups for 5 drugs: the methylxanthines theophylline and caffeine, a nonxanthine psychomotor stimulant, d-amphetamine, and the adenosine analogs R(-)-N6-2-(phenylisopropyl)adenosine and 5'-(N-ethyl)carboxamidoadenosine. All drugs were injected i.p. and locomotor activity was measured for 30 min beginning 35 min later. Rats that were maintained chronically on theophylline were completely tolerant to the locomotor activity stimulant effects of acutely administered theophylline and cross-tolerant to caffeine-induced stimulation of locomotor activity. In contrast, both control and treated groups were fully responsive to the stimulant effects of d-amphetamine. Low doses of the adenosine analogs produced stimulation of locomotor activity in both groups of rats. Higher doses produced a dose-dependent depression of locomotor activity in control rats; curves for the theophylline-treated rats were shifted to the right of the control curves. Thus, adenosine antagonist activity of theophylline remained evident at a time of complete tolerance to the stimulant effect of the drug on locomotor activity.