Pharmacological evidence for different populations of postsynaptic adenosine A 2A receptors in the rat striatum

Abstract

Adenosine A 2A receptors (A 2ARs) are highly concentrated in the striatum. Two pharmacological different functional populations of A 2ARs have been recently described based on their different affinities for the A 2AR antagonist SCH-442416. This compound has high affinity for A 2ARs not forming heteromers or forming heteromers with adenosine A 1 receptors (A 1Rs) while showing very low affinity for A 2ARs forming heteromers with dopamine D 2 receptors (D 2Rs). It has been widely described that striatal A 1R–A 2AR heteromers are preferentially localized presynaptically in the glutamatergic terminals that contact GABAergic dynorphinergic neurons, and that A 2AR–D 2R heteromers are localized postsynaptically in GABAergic enkephalinergic neurons. In the present study we provide evidence suggesting that SCH-442416 also targets postsynaptic A 2AR not forming heteromers with D 2R, which are involved in the motor depressant effects induced by D 2R antagonists. SCH-442416 counteracted motor depression in rats induced by the D 2R antagonist raclopride at a dose that did not produce motor activation or that blocked motor depression induced by an A 2AR agonist. Furthermore, we re-evaluated the recently suggested key role of cannabinoid CB 1 receptors (CB 1Rs) in the effects of A 2AR antagonists acting at postsynaptic A 2ARs. By recording locomotor activity and monitoring striatal glutamate release induced by cortical electrical stimulation in rats after administration of A 2AR and CB 1R antagonists, we did not find evidence for any significant role of endocannabinoids in the post- or presynaptic effects of A 2AR antagonists. The present results further suggest the existence of at least two functionally and pharmacologically different populations of striatal postsynaptic A 2ARs.