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Phosphodiesterase-1b (Pde1b) knockout mice are resistant to forced swim and tail suspension induced immobility and show upregulation of Pde10a

Hufgard, Jillian R., Williams, Michael T., Skelton, Matthew R., Grubisha, Olivera ORCID:, Ferreira, Filipa M., Sanger, Helen, Wright, Mary E., Reed-Kessler, Tracy M., Rasmussen, Kurt, Duman, Ronald S. and Vorhees, Charles V. 2017. Phosphodiesterase-1b (Pde1b) knockout mice are resistant to forced swim and tail suspension induced immobility and show upregulation of Pde10a. Psychopharmacology 234 10.1007/s00213-017-4587-8

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Rationale Major depressive disorder is a leading cause of suicide and disability. Despite this, current antidepressants provide insufficient efficacy in more than 60% of patients. Most current antidepressants are presynaptic reuptake inhibitors; postsynaptic signal regulation has not received as much attention as potential treatment targets. Objectives We examined the effects of disruption of the postsynaptic cyclic nucleotide hydrolyzing enzyme, phosphodiesterase (PDE) 1b, on depressive-like behavior and the effects on PDE1B protein in wild-type (WT) mice following stress. Methods Littermate knockout (KO) and WT mice were tested in locomotor activity, tail suspension (TST), and forced swim tests (FST). FST was also used to compare the effects of two antidepressants, fluoxetine and bupropion, in KO versus WT mice. Messenger RNA (mRNA) expression changes were also determined. WT mice underwent acute or chronic stress and markers of stress and PDE1B expression were examined. Results Pde1b KO mice exhibited decreased TST and FST immobility. When treated with antidepressants, both WT and KO mice showed decreased FST immobility and the effect was additive in KO mice. Mice lacking Pde1b had increased striatal Pde10a mRNA expression. In WT mice, acute and chronic stress upregulated PDE1B expression while PDE10A expression was downregulated after chronic but not acute stress. Conclusions PDE1B is a potential therapeutic target for depression treatment because of the antidepressant-like phenotype seen in Pde1b KO mice.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Biosciences
Publisher: Springer Verlag (Germany)
ISSN: 0033-3158
Date of First Compliant Deposit: 12 November 2019
Date of Acceptance: 1 March 2017
Last Modified: 07 Nov 2023 01:36

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