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

Adenosine A(2A) receptors (A(2A)Rs) are highly concentrated in the striatum. Two pharmacological different functional populations of A(2A)Rs have been recently described based on their different affinities for the A(2A)R antagonist SCH-442416. This compound has high affinity for A(2A)Rs not forming heteromers or forming heteromers with adenosine A(1) receptors (A(1)Rs) while showing very low affinity for A(2A)Rs forming heteromers with dopamine D-2 receptors (D(2)Rs). It has been widely described that striatal A(1)R-A(2A)R heteromers are preferentially localized presynaptically in the glutamatergic terminals that contact GABAergic dynorphinergic neurons, and that A(2A)R-D2R heteromers are localized postsynaptically in GABAergic enkephalinergic neurons. In the present study we provide evidence suggesting that SCH-442416 also targets postsynaptic A(2A)R 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 A(2A)R agonist. Furthermore, we re-evaluated the recently suggested key role of cannabinoid CB1 receptors (CB1 Rs) in the effects of A(2A)R antagonists acting at postsynaptic A(2A)Rs. By recording locomotor activity and monitoring striatal glutamate release induced by cortical electrical stimulation in rats after administration of A(2A)R and CB1R antagonists, we did not find evidence for any significant role of endocannabinoids in the post- or presynaptic effects of A(2A)R antagonists. The present results further suggest the existence of at least two functionally and pharmacologically different populations of striatal postsynaptic A(2A)Rs. Published by Elsevier Ltd.