Inhibition of Adenosine Deaminase by Erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA) Mimics the Effect of Inescapable Shock on Escape Learning in Rats

Three experiments examined the role of adenosine neuroregulation in the production of shuttle-escape deficits caused by prior exposure to inescapable electric shock in rats (learned helplessness). Intracerebroventricular administration of erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA), a selective adenosine deaminase inhibitor, mimicked the effect of earlier inescapable shock at a dose of 2.5 μM in previously restrained rats. Performance deficits produced by EHNA or by earlier exposure to inescapable shock were reversed by intraperitoneal injection of 10 mg/kg caffeine, an adenosine receptor antagonist. Finally, preexposure to an ineffective number of shocks interacted in synergy with an ineffective pretest dose (1.0 μM) of EHNA to maximize shuttle-escape latencies. These data implicate endogenous adenosine neuroregulation as a proximate mechanism in learned helplessness and conservation-withdrawal.