We examined the relationship between metabolic stress, brain adenosine regulation, and the learned helplessness effect in four experiments in rats. Glucoprivation and metabolic inhibition were induced by treating previously restrained (nonshocked) rats with 2-deoxy-D-glucose (2DG) shortly before escape testing. Experiment 1 demonstrated that 2-deoxy-D-glucose impairs escape performance in a dose-dependent manner. Experiment 2 showed that 2-deoxy-D-glucose and shock induced escape deficits are completely reversed by peripheral administration of the adenosine receptor antagonist caffeine. This result indicates that both inescapable shock and 2-deoxy-D-glucose result in compensatory adenosine regulation which, in turn, mediates the behavioral impairment. Experiment 3 determined that 8-[p-sulfophenyl]-theophylline, a peripheral adenosine receptor antagonist, fails to reverse the escape deficit resulting from metabolic stress, whereas centrally acting theophylline does. Experiment 4 showed that the behavioral impairments from both 2-deoxy-D-glucose and inescapable shock are reversed by intracranial ventricular (icv) caffeine treatment. The results of Experiments 3 and 4 indicate that the enhanced adenosine regulation and the ensuing performance deficit resulting from 2-deoxy-D-glucose treatment occurred in the central nervous system. These data are discussed in terms of the metabolic demands of neuronal over-activation during escape testing in inescapably shocked rats and the loss of normal behavioral function due to compensatory adenosine regulation in the brain.