Phosphodiesterase 1B differentially modulates the effects of methamphetamine on locomotor activity and spatial learning through DARPP32-dependent pathways: evidence from PDE1B-DARPP32 double-knockout mice.
Mice lacking phosphodiesterase 1B (PDE1B) exhibit an exaggerated locomotor response to D-methamphetamine and increased in vitro phosphorylation of DARPP32 (dopamine- and cAMP-regulated phosphoprotein, M r 32 kDa) at Thr34 in striatal brain slices treated with the D1 receptor agonist, SKF81297. These results indicated a possible regulatory role for PDE1B in pathways involving DARPP32. Here, we generated PDE1B x DARPP32 double-knockout (double-KO) mice to test the role of PDE1B in DARPP32-dependent pathways in vivo. Analysis of the response to d-methamphetamine on locomotor activity showed that the hyperactivity experienced by PDE1B mutant mice was blocked in PDE1B-/- x DARPP32-/- double-KO mice, consistent with participation of PDE1B and DARPP32 in the same pathway. Further behavioral testing in the elevated zero-maze revealed that DARPP32-/- mice showed a less anxious phenotype that was nullified in double-mutant mice. In contrast, in the Morris water maze, double-KO mice showed deficits in spatial reversal learning not observed in either single mutant compared with wild-type mice. The data suggest a role for PDE1B in locomotor responses to psychostimulants through modulation of DARPP32-dependent pathways; however, this modulation does not necessarily impact other behaviors, such as anxiety or learning. Instead, the phenotype of double-KOs observed in these latter tasks may be mediated through independent pathways.
Ehrman
L A
LA
Division of Developmental Biology, Division of Neurology, Cincinnati Children's Research Foundation and University of Cincinnati College of Medicine, Cincinnati, OH 45229-3039, USA.
Williams
M T
MT
Schaefer
T L
TL
Gudelsky
G A
GA
Reed
T M
TM
Fienberg
A A
AA
Greengard
P
P
Vorhees
C V
CV
D000704:Analysis of Variance; D000818:Animals; D001007:Anxiety / Q000378:metabolism; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D054677:Cyclic Nucleotide Phosphodiesterases, Type 1; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32 / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006948:Hyperkinesis / Q000201:enzymology / Q000235:genetics; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D008694:Methamphetamine / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects* / Q000502:physiology; D010727:Phosphoric Diester Hydrolases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D013037:Spatial Behavior / Q000187:drug effects* / Q000502:physiology
D000697:Central Nervous System Stimulants; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; C497929:Ppp1r1b protein, mouse; D008694:Methamphetamine; D010727:Phosphoric Diester Hydrolases; D054677:Cyclic Nucleotide Phosphodiesterases, Type 1; C517267:Pde1b protein, mouse