Methylxanthines elevate reinforcement threshold for electrical brain stimulation: role of adenosine receptors and phosphodiesterase inhibition.

Caffeine increases reinforcement threshold in a brain stimulation procedure that allows the rat to self-regulate the intensity of electric current delivered via an electrode in the medial forebrain bundle. In order to determine the generality of that finding, we used this same autotitration procedure to assess the behavioral effects of 5 methylxanthines in addition to caffeine. All of the methylxanthines produced significant dose-dependent elevations of reinforcement threshold with the following order of potency: 7-(beta-chloroethyl)theophylline greater than isobutylmethyl-xanthine greater than 1,7-dimethylxanthine greater than theophylline greater than caffeine greater than 8-chlorotheophylline. This order of potency correlates significantly with the reported order of potency for inhibiting adenosine-stimulated cAMP, an effect mediated by the adenosine A2 receptor. Some of the behavioral effects of methylxanthines have been attributed to antagonism of adenosine receptor binding and inhibition of phosphodiesterase. The nonxanthine phosphodiesterase inhibitors papaverine and Ro 20-1724, had small but significant effects on reinforcement threshold, papaverine increasing it and Ro 20-1724 decreasing it. Thus, as a pharmacologic class, methylxanthines appear to increase reinforcement threshold, an effect which may be mediated via adenosine receptor antagonism but probably not by inhibition of phosphodiesterase.