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The Journal of Neuroscience, June 15, 2002, 22(12):5188-5197

Phosphodiesterase 1B Knock-Out Mice Exhibit Exaggerated Locomotor Hyperactivity and DARPP-32 Phosphorylation in Response to Dopamine Agonists and Display Impaired Spatial Learning

Tracy M. Reed^{1, 3}, David R. Repaske^{2, *}, Gretchen L. Snyder⁴, Paul Greengard⁴, and Charles V. Vorhees^{1, *}

Divisions of ¹ Developmental Biology and ² Endocrinology, Children's Hospital Research Foundation, Cincinnati, Ohio 45229, ³ Department of Biology, College of Mount St. Joseph, Cincinnati, Ohio 45233, and ⁴ Laboratory of Molecular and Cellular Neuroscience, Rockefeller University, New York, New York 10021

Using homologous recombination, we generated mice lacking phosphodiesterase-mediated (PDE1B) cyclic nucleotide-hydrolyzing activity. PDE1B^/ mice showed exaggerated hyperactivity after acute D-methamphetamine administration. Striatal slices from PDE1B^/ mice exhibited increased levels of phospho-Thr³⁴ DARPP-32 and phospho-Ser⁸⁴⁵ GluR1 after dopamine D1 receptor agonist or forskolin stimulation. PDE1B^/ and PDE1B^+/ mice demonstrated Morris maze spatial-learning deficits. These results indicate that enhancement of cyclic nucleotide signaling by inactivation of PDE1B-mediated cyclic nucleotide hydrolysis plays a significant role in dopaminergic function through the DARPP-32 and related transduction pathways.

Key words: phosphodiesterases; DARPP-32; dopamine-stimulated locomotor activity; spatial learning and memory; Morris water maze; methamphetamine; SKF81297; forskolin

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^* D.R.R. and C.V.V. contributed equally to this work.

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Copyright © 2002 Society for Neuroscience  0270-6474/02/22125188-10$05.00/0

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