Striatal adenosine A2A receptors

Abstract

The nucleoside adenosine exerts a modulatory action in the central nervous system by activating G-protein coupled receptors. Four such receptors are cloned and pharmacologically characterized: A1, A2A, A2B and A3. Caffeine, the most widely consumed psychostimulant, acts as an adenosine receptor antagonist predominantly on the first two. Adenosine A1 receptors influence neuronal excitability and neurotransmitter release in an inhibitory manner and are expressed in most brain areas. On the other hand, adenosine A2A receptors, the subject of the present thesis, are predominantly expressed in striatum, the major area of the basal ganglia. Striatum processes sensorimotor, associative and limbic information that it receives in a topographically organized way from cerebral cortex, thalamic subnuclei and the midbrain. Striatal efferents go to substantia nigra and the internal part of globus pallidus (the entopeduncular nucleus in rodents) either directly (the striatonigral pathway), or indirectly, via the external part of globus pallidus and the subthalamic nucleus (the striatopallidal pathway). By combining radioactive and non-radioactive in situ hybridization and highly sensitive riboprobes, A2A receptor mRNA was found, in primates as well as rodents, to be extensively co-expressed with dopamine D2 receptor mRNA in striatopallidal neurons, but not in cholinergic interneurons. A2A receptor mRNA was largely segregated from dopamine D1 receptor mRNA. The phosphoprotein DARPP-32 is highly enriched in striatal projection neurons and plays an important role in integrating intracellular responses exerted by the major striatal neurotransmitters, neuromodulators and neuropeptides. In striatal slices, simultaneous stimulation of A2A and D1 receptors was found to exert an additive effect on phosphorylation, and thereby activation, of DARPP-32, suggesting that A2A receptors regulate the activity of DARRP-32 in the striatopallidal pathway and that D1 receptors do so in the striatonigral. The present study also shows that the biphasic effect of caffeine on locomotion is mirrored by a biphasic regulation of immediate early genes in striatum. Blockade of adenosine A2A receptors appears crucial for the stimulatory action of caffeine. Our data suggest that endogenous adenosine, acting via A2A receptors, has a facilatatory effect on the expression of immediate early genes in the striatopallidal pathway that does not require intact dopaminergic neurotransmission. A2A receptors are, therefore, likely to be important for coordinating neurotransmission through the basal ganglia in a parallel manner. However, there are also important network interactions between adenosine A2A receptors and dopamine D1 receptors on immediate early gene expression in striatum and globus pallidus, partly resembling those between D1 and D2 receptors. In conclusion, these studies strongly suggest that endogenous adenosine, acting via A2A receptors, is of considerable importance for regulating neurotransmission in the striatopallidal pathway. The stimulation by caffeine in doses resembling those achieved following normal human use appears largely due to modulation of this pathway. These results further imply that adenosine A2A receptors may be a possible target for future development of drugs for treatment of Parkinson's disease, affective disorders and schizophrenia.