Escape deficits induced by inescapable shock and metabolic stress are reversed by adenosine receptor antagonists

We examined the relationship between metabolic stress. brain adenosine regu lation, and the learned helplessness effect in four experiments in rats. Gl ucoprivation and metabolic inhibition were induced by treating previously r estrained (nonshocked) rats with 2-deoxy-D-glucose (2DG) shortly before esc ape testing. Experiment 1 demonstrated that 2-deoxy-D-glucose impairs escap e performance in a dose-dependent manner. Experiment 2 showed that 2-deoxy- D-glucose and shock induced escape deficits are completely reversed by peri pheral administration of the adenosine receptor antagonist caffeine. This r esult 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 defic it resulting from metabolic stress. whereas centrally acting theophylline d oes. Experiment 4 showed that the behavioral impairments from both 2-deoxy- D-glucose and inescapable shock are reversed by intracranial ventricular (i cv) caffeine treatment. The results of Experiments 3 and 4 indicate that th e enhanced adenosine regulation and the ensuing performance deficit resulti ng from 2-deoxy-D-glucose treatment occurred in the central nervous system. These data are discussed in terms of the metabolic demands of neuronal ove r-activation during escape testing in inescapably shocked rats and the loss of normal behavioral function due to compensatory adenosine regulation in the brain. (C) 2001 Elsevier Science B.V. All rights reserved.