Adenosine A2 receptors regulate the gene expression of striatopallidal and striatonigral neurons

Abstract

Adenosine acts as a neuromodulator through A1 and A2 receptors. The adenosine analogs have been recognized, among other effects, as strong depressors of the locomotor activity by acting on striatal A2 receptors. Moreover, the A2a receptor subtype is exclusively expressed in the striatum. To elucidate at the cellular level the roles of adenosine in the basal ganglia, the anatomical and functional relationships of the A2 receptors with the dopamine D1 and D2 receptors were studied in the rat striatum. In situ hybridization histochemistry was used either in combination with retrograde labeling of striatonigral neurons to determine the projection site of A2a receptor expressing neurons, or on consecutive thin sections to address the putative coexpression of the A2a receptor with the D1 or D2 receptors in individual neurons. The A2a receptor is mainly expressed by neurons projecting to the globus pallidus and expressing also the dopamine D2 receptor and enkephalin, but very sparsely by neurons projecting to the substantia nigra that express the dopamine D1 receptor and substance P. We have further examined the regulatory effect of the A2 receptors on striatal gene expression using in situ hybridization histochemistry and quantitative autoradiography. Rats unilaterally depleted in dopamine by an unilateral 6-hydroxydopamine-induced lesion of the nigrostriatal pathway used as a model of Parkinson's disease subsequently received chronic injections of saline or the adenosine receptor antagonist caffeine. Intact rats were chronically treated with either saline, caffeine alone, caffeine with N-ethylcarboxamidoadenosine (an equipotent A, and A2 agonist), or caffeine with cyclohexyladenosine (a more selective A1 agonist). In striatopallidal neurons, caffeine reverses the alterations of enkephalin gene expression induced by the unilateral depletion in striatal dopamine while it has no effect on the alterations of substance P gene expression in striatonigral neurons. Conversely, in the intact striatum, normally innervated by dopaminergic fibers, caffeine acting through an A2 receptor induces similar alterations of enkephalin and substance P gene expression compared with the case of dopamine depletion. This suggests that adenosine and the widely consumed adenosine antagonist caffeine regulate through A2 receptors the gene expression of striatal neurons both by post- and presynaptic mechanisms.