QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

HOME  |   SEARCH  |   ARCHIVE  |   SUBSCRIBE  |   CONTACT  |   HELP

The Journal of Neuroscience, November 9, 2005, 25(45):10414-10419; doi:10.1523/JNEUROSCI.3660-05.2005

This Article Full Text Full Text (PDF) HTML Page - index.htslp Submit an eLetter Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (30) Citing Articles via Google Scholar Google Scholar Articles by Kachroo, A. Articles by Schwarzschild, M. A. Search for Related Content PubMed PubMed Citation Articles by Kachroo, A. Articles by Schwarzschild, M. A.

 Previous Article  |  Next Article 

Neurobiology of Disease
Interactions between Metabotropic Glutamate 5 and Adenosine A_2A Receptors in Normal and Parkinsonian Mice

Anil Kachroo,¹ Lianna R. Orlando,¹ David K. Grandy,² Jiang-Fan Chen,¹ Anne B. Young,¹ and Michael A. Schwarzschild¹

¹MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts 02129, and ²Department of Physiology and Pharmacology, Oregon Health Sciences University, Portland, Oregon 97201

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 D₂ 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.

Key words: metabotropic; adenosine; Parkinson's disease; knock-out; locomotion; G-protein-coupled receptor

---

Received April 26, 2005; revised September 14, 2005; accepted September 19, 2005.

This article has been cited by other articles:

				M. Day, D. Wokosin, J. L. Plotkin, X. Tian, and D. J. Surmeier Differential Excitability and Modulation of Striatal Medium Spiny Neuron Dendrites J. Neurosci., November 5, 2008; 28(45): 11603 - 11614. [Abstract] [Full Text] [PDF]

				T. Shindou, G. W. Arbuthnott, and J. R. Wickens Actions of Adenosine A2A Receptors on Synaptic Connections of Spiny Projection Neurons in the Neostriatal Inhibitory Network J Neurophysiol, April 1, 2008; 99(4): 1884 - 1889. [Abstract] [Full Text] [PDF]

				G. Burnstock Physiology and Pathophysiology of Purinergic Neurotransmission Physiol Rev, April 1, 2007; 87(2): 659 - 797. [Abstract] [Full Text] [PDF]

				D. Xiao, E. Bastia, Y.-H. Xu, C. L. Benn, J.-H. J. Cha, T. S. Peterson, J.-F. Chen, and M. A. Schwarzschild Forebrain Adenosine A2A Receptors Contribute to L-3,4-Dihydroxyphenylalanine-Induced Dyskinesia in Hemiparkinsonian Mice J. Neurosci., December 27, 2006; 26(52): 13548 - 13555. [Abstract] [Full Text] [PDF]

Home  |   Search  |   Archive  |   Subscribe  |   Contact  |   Help