Functional striatal hypodopaminergic activity in mice lacking adenosine A(2A) receptors

Adenosine and caffeine modulate locomotor activity and striatal gene expres sion, partially through the activation and blockade of striatal A(2A) recep tors, respectively. The elucidation of the roles of these receptors benefit s from the construction of A(2A) receptor-deficient mice (A(2A)-R-/-). Thes e mice presented alterations in locomotor behaviour and striatal expression of genes studied so far, which are unexpected regarding the specific expre ssion of A(2A) receptor by striatopallidal neurones. To clarify the functio ns of A(2A) receptors in the striatum and to identify the mechanisms leadin g to these unexpected modifications, we studied the basal expression of imm ediate early and constitutive genes as well as dopamine and glutamate neuro transmission in the striatum. Basal zif268 and arc mRNAs expression was red uced in mutant mice by 60-80%, not only in the striatum but also widespread in the cerebral cortex and hippocampus, Striatal expression of substance P and enkephalin mRNAs was reduced by about 50% and 30%, respectively, where as the expression of GAD67 and GAD65 mRNAs was slightly increased and unalt ered, respectively. In vivo microdialysis in the striatum revealed a 45% de crease in the extracellular dopamine concentration and three-fold increase in extracellular glutamate concentration. This was associated with an up-re gulation of D-1 and D-2 dopamine receptors expression but not with changes in ionotropic glutamate receptors, The levels of tyrosine hydroxylase and o f striatal and cortical glial glutamate transporters as well as adenosine A (1) receptors expression were indistinguishable between A(2A)-R-/- and wild -type mice. Altogether these results pointed out that the lack of A(2A) rec eptors leads to a functional hypodopaminergic state and demonstrated that A (2A) receptors are necessary to maintain a basal level in immediate early a nd constitutive genes expression in the striatum and cerebral cortex, possi bly via their control of dopamine pathways.