A2A adenosine receptor ligands: effects on alcohol intake in alcohol-preferring rats

Increasing evidence relates A2A adenosine receptors (ARs) with several pathological conditions such as neurodegenerative disorders, drug addition, inflammation, and pharmacological stress. SARs of ligands at the A2AAR indicate that substitution of adenosine at the 2-position, especially with (thio)ethers, secondary amines, and alkynes combined with a 5′-Nethyluronamide led to selective agonists. These two modifications are present in the widely used A2AAR agonist CGS 21680 and in another agonist named VT 7, synthesized in our lab. On the other hand, substitution of the adenosine ribose moiety with alkyl chains combined with the introduction of suitable substituents at the adenine core resulted in A2AAR antagonists, as in the case of ANR 94. Here, the effect of CGS 21680, VT 7, and of ANR 94 on voluntary drinking and operant self-administration of 10% ethanol in Marchigian Sardinian alcohol-preferring (msP) rats was evaluated. Results provide evidence that A2AAR agonists markedly attenuate both voluntary drinking and operant ethanol self-administration in msP rats. In particular, the A2AAR agonist VT 7, differently from CGS 21680, was able to evoke an effect on alcohol consumption, which does not significantly affect locomotor activity, so proving to be behaviourally selective. Thus, A2AARs may represent a potential target for the alcohol abuse and alcoholism treatment.