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

Anil Kachroo, Lianna R. Orlando, David K. Grandy, Jiang Fan Chen, Anne B. Young, Michael A. Schwarzschild

Research output: Contribution to journalArticlepeer-review

122 Scopus citations

Abstract

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 A2A 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 A2A and D 2 receptor KO mice. In contrast, motor stimulation by a D1 dopamine agonist was not attenuated in the KO mice. The A2A 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 A2A receptors. The potentiation of mGlu5 antagonist-induced motor stimulation by an A2A antagonist and its dependence on both D2 and forebrain A2A 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 A2A and mGlu5 antagonists.

Original languageEnglish (US)
Pages (from-to)10414-10419
Number of pages6
JournalJournal of Neuroscience
Volume25
Issue number45
DOIs
StatePublished - Nov 9 2005
Externally publishedYes

Keywords

  • Adenosine
  • G-protein-coupled receptor
  • Knock-out
  • Locomotion
  • Metabotropic
  • Parkinson's disease

ASJC Scopus subject areas

  • Neuroscience(all)

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