Journal
JOURNAL OF NEUROSCIENCE
Volume 22, Issue 12, Pages 5188-5197Publisher
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.22-12-05188.2002
Keywords
phosphodiesterases; DARPP-32; dopamine-stimulated locomotor activity; spatial learning and memory; Morris water maze; methamphetamine; SKF81297; forskolin
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Funding
- NIDA NIH HHS [DA10044, P01 DA010044, R01 DA06733, R01 DA006733] Funding Source: Medline
- NIEHS NIH HHS [T32 ES07051, T32 ES007051] Funding Source: Medline
- NIMH NIH HHS [MH40899, P01 MH040899] Funding Source: Medline
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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-Thr(34) DARPP-32 and phospho-Ser(845) 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.
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