@article{8d0ee44664f041c5bf10536e54ee037a,
title = "Involvement of DARPP-32 phosphorylation in the stimulant action of caffeine",
abstract = "Caffeine has been imbibed since ancient times in tea and coffee, and more recently in colas. Caffeine owes its psychostimulant action to a blockade of adenosine A2A receptors, but little is known about its intracellular mechanism of action. Here we show that the stimulatory effect of caffeine on motor activity in mice was greatly reduced following genetic deletion of DARPP-32 (dopamine- and cyclic AMP-regulated phosphoprotein of relative molecular mass 32, 000). Results virtually identical to those seen with caffeine were obtained with the selective A2A antagonist SCH 58261. The depressant effect of the A2A receptor agonist, CGS 21680, on motor activity was also greatly attenuated in DARPP-32 knockout mice. In support of a role for DARPP-32 in the action of caffeine, we found that, in striata of intact mice, caffeine increased the state of phosphorylation of DARPP-32 at Thr 75. Caffeine increased Thr 75 phosphorylation through inhibition of PP-2A-catalysed dephosphorylation, rather than through stimulation of cyclin-dependent kinase 5 (Cdk5)-catalysed phosphorylation, of this residue. Together, these studies demonstrate the involvement of DARPP-32 and its phosphorylation/dephosphorylation in the stimulant action of caffeine.",
author = "Maria Lindskog and Per Svenningsson and Laura Pozzi and Yong Kim and Flenberg, {Allen A.} and Bibb, {James A.} and Fredholm, {Bertil B.} and Nairn, {Angus C.} and Paul Greengard and Gilberto Fisone",
note = "Funding Information: We thank R. Rimondini and S.-O. {\"O}gren for help in performing behavioural experiments and A. Nishi for discussions. This work was supported by the Swedish Research Council (G.F. and B.B.F.), the Swedish Society for Medical Research (M.L.), the Foundation Blanceflor Boncompagni-Ludovisi, n{\'e}e Bildt (L.P.) and by funding from the National Institute of Mental Health and the National Institute of Drug Abuse (A.C.N. and P.G.). Funding Information: We acknowledge the contributions of more than 50 field assistants in Peru, Ecuador and Bolivia, the residents of Constancia, Infierno, La Torre, Mishana and Florida, as well as logistical support from Instituto Nacional de Recursos Naturales (INRENA), Amazon Center for Environmental Education and Research (ACEER), Cuzco Amaz{\'o}nico Lodge, Explorama Tours SA, Instituto de Investigaciones de la Amazon{\'i}a Peruana (IIAP), Parque Nacional Noel Kempff, Peruvian Safaris SA, Universidad Nacional de la Amazon{\'i}a Peruana, and Universidad Nacional de San Antonio Abad del Cusco. Field research was supported by the EU Fifth Framework Programme (RAINFOR), the UK Natural Environment Research Council, the National Geographic Society, the American Philosophical Society, the National Science Foundation, the WWF-U.S./ Garden Club of America, Conservation International, the MacArthur and Mellon Foundations, US-AID, the Max-Planck Institute for Biogeochemistry and the Royal Society (Y.M.). The manuscript benefited from comments by C. K{\"o}rner and N. Pitman. We are indebted to the late A.H. Gentry for helping to make this work possible.",
year = "2002",
month = aug,
day = "15",
doi = "10.1038/nature00817",
language = "English (US)",
volume = "418",
pages = "774--778",
journal = "Nature",
issn = "0028-0836",
publisher = "Nature Publishing Group",
number = "6899",
}