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The Journal of Neuroscience, December 15, 1999, 19(24):11017-11026

Role of Adenosine A2 Receptors in Brain Stimulation Reward under Baseline Conditions and during Cocaine Withdrawal in Rats

Brian A. Baldo, George F. Koob, and Athina Markou

Division of Psychopharmacology, Department of Neuropharmacology, The Scripps Research Institute, La Jolla, California 92037, and Program in Neurosciences, Department of Neuroscience, University of California, San Diego School of Medicine, La Jolla, California 92093

The present experiments tested the hypothesis that adenosine A2 receptors are involved in central reward function. Adenosine receptor agonists or antagonists were administered to animals that had been trained to self-stimulate in a rate-free brain stimulation reward (BSR) task that provides current thresholds as a measure of reward. The adenosine A_2A receptor-selective agonists 2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxamido adenosine hydrochloride (CGS 21680) (0.1-1.0 mg/kg) and 2-[(2-aminoethylamino)carbonylethyl phenylethylamino]-5'-N-ethylcarboxamido adenosine (APEC) (0.003-0.03 mg/kg) elevated reward thresholds without increasing response latencies, a measure of performance. Specifically, CGS 21680 had no effect on response latency, whereas APEC shortened latencies. Bilateral infusion of CGS 21680 (3, 10, and 30 ng/side), directly into the nucleus accumbens, elevated thresholds but shortened latencies. The highly selective A_2A antagonist 8-(3-chlorostyryl)caffeine (0.01-10.0 mg/kg) and the A2-preferring antagonist 3,7-dimethyl-1-propargylxanthine (DMPX) (0.3-10.0 mg/kg) did not alter thresholds or latencies, but DMPX (1.0, 10.0 mg/kg) blocked the threshold-elevating effect of APEC (0.03 mg/kg). In another study, repeated administration of cocaine (eight cocaine injections of 15 mg/kg, i.p., administered over 9 hr) produced elevations in thresholds at 4, 8, and 12 hr after cocaine. DMPX (3 and 10 mg/kg), administered before both the 8 and 12 hr post-cocaine self-stimulation tests, reversed the threshold elevation produced by cocaine withdrawal. These results indicate that stimulating adenosine A_2A receptors diminishes BSR without producing performance deficits, whereas blocking adenosine receptors reverses the reward impairment produced by cocaine withdrawal or by an A_2A agonist. These findings indicate that adenosine, via A_2A receptors, may inhibit central reward processes, particularly during the neuroadaptations associated with chronic drug-induced neuronal activation.

Key words: adenosine; adenosine A_2A receptor; dopamine; brain stimulation reward; nucleus accumbens; cocaine; withdrawal; DMPX; CGS 21680; APEC; chlorostyryl-caffeine

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Copyright © 1999 Society for Neuroscience  0270-6474/99/192411017-10$05.00/0

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