Adenosine A2A receptor agonists increase Fos-like immunoreactivity in mesolimbic areas

Expression of the early-gene c-fos is an useful method for studying potential sites of action of drugs active in the CNS. Stimulation of adenosine A2A receptors by CGS 21680 (5 mg/kg) induced an increase in Fos-like immunoreactivity in the rat nucleus accumbens shell, while in the rostral pole and core CGS 21680 induced Fos-like immunoreactivity only after a high dose. CGS 21680 (5 mg/kg) stimulated c-fos expression also in the lateral septal nucleus and dorso-medial striatum, but not in the dorso-lateral striatum. A similar pattern of Fos-like immunoreactivity was obtained after administration of the A2A agonist HENECA (5 mg/kg) which displays higher selectivity for A2A receptors than CGS 21680. Administration of the selective A2A antagonist SCH 58261 counteracted CGS 21680-induced Fos-like immunoreactivity. Lesions of the dopaminergic mesostriatal projection by 6-hydroxydopamine and stimulation of dopamine D2/D3 receptors by quinpirole, prevented CGS 21680-induced Fos-like immunoreactivity in the nucleus accumbens shell. The present results show that stimulation of A2A receptors induces a profile of c-fos expression similar to that of atypical neuroleptics. A2A receptor stimulation has been reported to have dopamine antagonistic actions, it is therefore suggested that A2A agonists might have antipsychotic activity without producing extrapyramidal side effects.