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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, Mr 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 × 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.