Abstract
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.
Publication types
-
Research Support, Non-U.S. Gov't
-
Research Support, U.S. Gov't, P.H.S.
MeSH terms
-
Animals
-
Behavior, Animal
-
Brain / metabolism
-
Cyclic AMP-Dependent Protein Kinases / metabolism
-
Cyclic Nucleotide Phosphodiesterases, Type 1
-
Dopamine and cAMP-Regulated Phosphoprotein 32
-
Female
-
Gene Targeting
-
Kinetics
-
Male
-
Maze Learning
-
Memory
-
Mice
-
Mice, Knockout
-
Motor Activity*
-
Nerve Tissue Proteins*
-
Phosphoproteins / metabolism*
-
Phosphoric Diester Hydrolases / genetics*
-
Phosphoric Diester Hydrolases / physiology*
-
Phosphorylation
-
RNA, Messenger / biosynthesis
-
Receptors, Dopamine D1 / agonists*
Substances
-
Dopamine and cAMP-Regulated Phosphoprotein 32
-
Nerve Tissue Proteins
-
Phosphoproteins
-
RNA, Messenger
-
Receptors, Dopamine D1
-
Cyclic AMP-Dependent Protein Kinases
-
Phosphoric Diester Hydrolases
-
Cyclic Nucleotide Phosphodiesterases, Type 1
-
Pde1b protein, mouse