Interactions between metabotropic glutamate 5 and adenosine A2A receptors in normal and parkinsonian mice

Evidence for heteromeric receptor complexes comprising adenosine A(2A) and metabotropic glutamate 5 ( mGlu5) receptors in striatum has raised the possibility of synergistic interactions between striatal A2A and mGlu5 receptors. We investigated the role of striatal A2A receptors in the locomotor stimulant and antiparkinsonian properties of mGlu5 antagonists using complementary pharmacologic and genetic approaches. Locomotion acutely stimulated by the mGlu5 antagonist [2- methyl-6-( phenylethynyl)-pyridine (MPEP)] was absent in mGlu5 knock-out (KO) mice and was potentiated by an A(2A) antagonist KW-6002 [(E)-1,3-diethyl-8-(3,4-dimethoxystyryl)-7methylxanthine], both in normal and in dopamine-depleted (reserpinized) mice. Conversely, the MPEP-induced motor response was markedly attenuated in single and doubleA2A and D2 receptorKOmice. In contrast, motor stimulation by aD1 dopamine agonist was not attenuated in the KO mice. The A(2A) receptor dependence of MPEP- induced motor stimulation was investigated further using a postnatal forebrain- specific conditional ( Cre/ loxP system) KO of the A(2A) receptor. MPEP loses the ability to stimulate locomotion in conditional KO mice, suggesting that this mGlu5 antagonist effect requires the postdevelopmental action of striatal A(2A) receptors. The potentiation of mGlu5 antagonist-induced motor stimulation by an A(2A) antagonist and its dependence on both D-2 and forebrain A(2A) receptors highlight the functional interdependence of these receptors. These data also strengthen a rationale for pursuing a combinational drug strategy for enhancing the antiparkinsonian effects of A(2A) and mGlu5 antagonists.