Enhancing Brain Adenosine Signaling With the Nucleoside Transport Blocker NBTI (S-(4-Nitrobenzyl)-6-Theoinosine) Mimics the Effects of Inescapable Shock on Later Shuttle-Escape Performance in Rats

• Published in: Behavioral neuroscience 2008-12, Vol.122 (6), p.1236-1247
• Main Authors: Minor, Thomas R, Rowe, Michael, Cullen, Patrick K, Furst, Stephanie
• Format: Article
• Language: English
• Subjects: Adenosine; Adenosine - metabolism; Adult and adolescent clinical studies; Analysis of Variance; Animal; Animals; Behavior, Animal - drug effects; Behavioral psychophysiology; Biological and medical sciences; Brain - drug effects; Brain - metabolism; Caffeine - pharmacology; Depression; Depression (Emotion); Electroshock - adverse effects; Escape Reaction - drug effects; Freezing Reaction, Cataleptic - drug effects; Freezing Reaction, Cataleptic - physiology; Fundamental and applied biological sciences. Psychology; Learned Helplessness; Male; Medical sciences; Mood disorders; Neural Receptors; Nucleoside Transport Proteins - antagonists & inhibitors; Phosphodiesterase Inhibitors - pharmacology; Psychology. Psychoanalysis. Psychiatry; Psychology. Psychophysiology; Psychopathology. Psychiatry; Rats; Rats, Sprague-Dawley; Reaction Time - drug effects; Signal Transduction - drug effects; Thioinosine - analogs & derivatives; Thioinosine - pharmacology; Xanthines - pharmacology
• ISSN: 0735-7044; 1939-0084
• DOI: 10.1037/a0013143

Experience with unsignaled, inescapable shock represents a profound challenge to brain metabolic function and physiology. The authors have argued that behavioral impairment following this traumatic stress is a consequence of enhanced brain adenosine signaling, which promotes metabolic recovery by profoundly inhibiting neural activation. The authors tested this hypothesis by artificially increasing extracellular brain adenosine concentration by blocking uptake transport with NBTI in rats given only restraint stress in five experiments. NBTI impaired shuttle-escape performance in the manner of inescapable shock in a dose-dependent manner and acted synergistically with an ineffective number of inescapable shocks to maximally impair test performance. These deficits produced by inescapable shock and NBTI were reversed by the nonselective adenosine receptor antagonist caffeine, and the highly selective A 2A receptor antagonist CSC (8-(3-chloro-styrl)caffeine). The highly selective A 1 receptor antagonist DPCPX (8-Cyclopentyl-1,3-Dipropylxanthine) failed to improve performance in rats preexposed to inescapable shock or pretreated with NBTI. These data suggest that enhanced adenosine signaling at a brain A 2A receptor impairs escape performance following inescapable shock in the learned helplessness paradigm.