Interactions between metabotropic glutamate 5 and adenosine A_2A 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 A _2A and mGlu5 receptors. We investigated the role of striatal A _2A 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)-7-methylxanthine], both in normal and in dopamine-depleted (reserpinized) mice. Conversely, the MPEP-induced motor response was markedly attenuated in single and double A_2A and D ₂ receptor KO mice. In contrast, motor stimulation by a D₁ 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 D2 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.