Pharmacological evidence for different populations of postsynaptic adenosine A2A receptors in the rat striatum

Adenosine A2A receptors (A2ARs) are highly concentrated in the striatum. Two pharmacological different functional populations of A2ARs have been recently described based on their different affinities for the A2AR antagonist SCH-442416. This compound has high affinity for A2ARs not forming heteromers or forming heteromers with adenosine A1 receptors (A1Rs) while showing very low affinity for A2ARs forming heteromers with dopamine D2 receptors (D2Rs). It has been widely described that striatal A1R–A2AR heteromers are preferentially localized presynaptically in the glutamatergic terminals that contact GABAergic dynorphinergic neurons, and that A2AR–D2R heteromers are localized postsynaptically in GABAergic enkephalinergic neurons. In the present study we provide evidence suggesting that SCH-442416 also targets postsynaptic A2AR not forming heteromers with D2R, which are involved in the motor depressant effects induced by D2R antagonists. SCH-442416 counteracted motor depression in rats induced by the D2R antagonist raclopride at a dose that did not produce motor activation or that blocked motor depression induced by an A2AR agonist. Furthermore, we re-evaluated the recently suggested key role of cannabinoid CB1 receptors (CB1Rs) in the effects of A2AR antagonists acting at postsynaptic A2ARs. By recording locomotor activity and monitoring striatal glutamate release induced by cortical electrical stimulation in rats after administration of A2AR and CB1R antagonists, we did not find evidence for any significant role of endocannabinoids in the post- or presynaptic effects of A2AR antagonists. The present results further suggest the existence of at least two functionally and pharmacologically different populations of striatal postsynaptic A2ARs.

► Adenosine A2A receptors are highly concentrated in the striatum.
► Presynaptic and postsynaptic A2A receptors can be differentiated pharmacologically.
► There are two subpopulations of postsynaptic A2A receptors.
► The two postsynaptic A2A receptors can also be differentiated pharmacologically.
► Endocannabinoids do not mediate locomotion induced by A2A receptor antagonists.