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The Journal of Neuroscience, January 24, 2007, 27(4):881-885; doi:10.1523/JNEUROSCI.5074-06.2007

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Brief Communications
Regulation of Akt Signaling by D₂ and D₃ Dopamine Receptors In Vivo

Jean-Martin Beaulieu,¹ Emanuele Tirotta,² Tatyana D. Sotnikova,¹ Bernard Masri,¹ Ali Salahpour,¹ Raul R. Gainetdinov,¹ Emiliana Borrelli,² and Marc G. Caron¹

¹Department of Cell Biology, Duke University Medical Center, Durham, North Carolina 27710, and ²Department of Psychiatry and Human Behavior, University of California Irvine, Irvine, California 92697

Correspondence should be addressed to Marc G. Caron, 487 Clinical and Research Labs Building, Box 3287, Duke University Medical Center, Research Drive, Durham, NC 27710. Email: m.caron{at}cellbio.duke.edu

The serine/threonine kinase Akt is a downstream target of dopamine receptor signaling that is inhibited/dephosphorylated in response to direct and indirect dopamine receptor agonists. Although pharmacological studies uncovered the involvement of D₂-class dopamine receptors in Akt regulation, they did not identify the role of individual receptor subtypes in this process. Here we used knock-out mice lacking the D₁, D₂, D₂ long, or D₃ dopamine receptors as well as a D₄ receptor-selective antagonist to address the function of each of these receptors in the regulation of Akt in vivo. Under basal conditions, D₂, D₂ long, and D₃ knock-out mice display enhanced striatal Akt activation, whereas D₁ knock-out mice and mice treated with the D₄ receptor antagonist L745870 (3-[[4-(4-chlorophenyl)piperazin-1-yl]methyl]-1H-pyrrolo[2,3-b]pyridine trihydrochloride) have phospho-Akt levels comparable with those of normal control animals. Furthermore, both amphetamine and apomorphine lose their ability to inhibit Akt in D₂ knock-out mice but retain their normal effect on this signaling molecule in D₁ knock-out animals. Finally, D₃ knock-out mice show a reduced sensitivity of Akt-mediated signaling to dopaminergic drugs but retain the action of these drugs on Akt at high dose regimens. These results indicate that D₂ receptors are essential for the inhibition of Akt by dopamine and that D₃ receptors also participate in this signaling potentially by enhancing D₂ receptor response. Identification of the functions of individual dopamine receptor subtypes in Akt regulation may help the development of new pharmaceutical approaches for mental disorders related to abnormal dopamine transmission such as bipolar disorder and schizophrenia.

Key words: dopamine; Akt; D₂ receptors; D₃ receptors; amphetamine; apomorphine; knock-out; signaling

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Received Aug. 23, 2006; accepted Dec. 12, 2006.

Correspondence should be addressed to Marc G. Caron, 487 Clinical and Research Labs Building, Box 3287, Duke University Medical Center, Research Drive, Durham, NC 27710. Email: m.caron{at}cellbio.duke.edu

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