Effect of the Adenosine A2a Receptor Antagonist 3,7‐Dimethyl‐Propargylxanthine on Anxiety‐like and Depression‐like Behavior and Alcohol Consumption in Wistar Rats

Abstract

It has been suggested that the reinforcing properties of ethanol are in part mediated via an A2 activation of cAMP/PKA signaling in the nucleus accumbens, predicting that administration of an A2a antagonist might reduce ethanol reward and consumption. We therefore examined the effect of the adenosine A2a receptor antagonist 3,7-dimethylpropargylxanthine (DMPX, 3, and 10 mg/kg intraperitoneal) on alcohol reinforcement, anxiety-related, depression, and rewarding behaviors in nonselected Wistar rats. Operant ethanol self-administration was used for examining alcohol intake, elevated plus-maze and Vogel conflict test for anxiety-related behavior, Porsolt swim test for depression-like behavior, and conditioned place preference for examination of the rewarding properties of the drug. 3,7-Dimethylpropargylxanthine decreased lever-pressing for ethanol in a dose-dependent manner. When analyzed as percentage of pretreatment baseline, maximum suppression was approximately 60% (39+/-7.5 vs 98+/-12%, mean+/-SEM, p=0.017). This effect was behaviorally specific, as no effect was found on the water lever. In agreement with previously published data, stimulation of locomotion was found (beam-breaks: 3590+/-540 vs 2475+/-240, 10 mg/kg vs saline, p=0.048). No anxiety-modulating effects were seen in either the elevated plus-maze or the Vogel conflict test. 3,7-Dimethylpropargylxanthine was not found to have intrinsic rewarding properties in the conditioned place preference model. In summary, DMPX produced a robust and behaviorally selective reduction of ethanol reinforcement, while anxiety-modulating effects were less consistent. These results bring further support to a role for adenosine in the regulation of ethanol consumption and possibly alcohol addiction/abuse, and the A2a receptor as a potential target for the treatment of alcoholism and alcohol abuse.