Selective adenosine A2A receptor/dopamine D2 receptor interactions in animal models of schizophrenia

In the apomorphine-induced climbing mouse assay, the potencies of the selective adenosine A1 receptor agonist, N6-cyclohexyladenosine (CHA), and the selective A2A adenosine receptor agonist, 2-p-(2-carboxyethyl) phenethylamino 5'-N-ethyl-carboxamidoadenosine (CGS 21680), and various dopamine receptor antagonists were as follows: SCH 23390 = haloperidol > raclopride > CHA = CGS 21680. While in catalepsy, their potencies were SCH 23390 > haloperidol > raclopride > CGS 21680. CHA failed to induce catalepsy due to significant sedation/ataxia. The combined administration of the ED15 dose of CHA failed to potentiate the ED50 value of SCH 23390, raclopride, or haloperidol in the apomorphine-induced climbing mouse assay. However, the combined administration of the ED15 dose of CGS 21680 significantly decreased the ED50 of raclopride by 8.0-fold and haloperidol by 35-fold. The adenosine A2A receptor antagonist, 1,3,7-trimethyl-8-(3-chlorostyryl)xanthine (CSC), significantly decreased catalepsy induced by raclopride and haloperidol, while the adenosine A1 receptor antagonist, 1,3-dimethyl-8-phenylxanthine (8-PT), was ineffective. The present results show that in behavioral assays predictive for antipsychotic activity, adenosine receptor agonists block behaviors in a similar manner to dopamine receptor antagonists.