Interactions between Metabotropic Glutamate 5 and Adenosine A 2A Receptors in Normal and Parkinsonian Mice

• Published in: The Journal of neuroscience 2005-11, Vol.25 (45), p.10414-10419
• Main Authors: Kachroo, Anil, Orlando, Lianna R., Grandy, David K., Chen, Jiang-Fan, Young, Anne B., Schwarzschild, Michael A.
• Format: Article
• Language: English
• ISSN: 0270-6474; 1529-2401
• DOI: 10.1523/JNEUROSCI.3660-05.2005

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 D 1 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.