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24704.pdf (4.74 MB)
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PDE1B KO Confers Resilience to Acute Stress-induced Depression-like Behavior
Author Info
Hufgard, Jillian R
ORCID® Identifier
http://orcid.org/0000-0002-6248-1087
Permalink:
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1504803606103525
Abstract Details
Year and Degree
2017, PhD, University of Cincinnati, Medicine: Molecular and Developmental Biology.
Abstract
Phosphodiesterases (PDE) regulate secondary messengers such as cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) by hydrolyzing the phosphodiester bond. There are over 100 PDE proteins that are categorized into 11 families. Each protein family has a unique tissue distribution and binding affinity for cAMP and/or cGMP. The modulation of different PDEs has been used to treat several disorders: inflammation, erectile dysfunction, and neurological disorders. Recently, PDE inhibitors were implicated for therapeutic benefits in Alzheimer’s disease, depression, Huntington’s disease, Parkinson’s disease, schizophrenia, and substance abuse. PDE1B is found in the caudate-putamen, nucleus accumbens, dentate gyrus, and substantia nigra–areas linked to depression. PDE1B expression is also increased after acute and chronic stress. Two ubiquitous Pde1b knockout (KO) mouse models, both removing part of the catalytic region, decreased immobility on two acute stress tests associated with depression-like behavior; tail suspension test (TST) and forced swim test (FST). The decreases in immobility suggest resistance to depression-like behavior, and these effects were additive when combined with two current antidepressants, fluoxetine and bupropion. The resistance to induced immobility was seen when PDE1B was knocked down during adolescence or earlier. Expression of Pde1b mRNA and protein showed that Pde1b is localized to dopaminergic and glutamatergic post-synaptic cells. Serotonin transporter, dopamine transporter, and dopamine receptor D1a (Drd1a) Cre drivers were tested and only Pde1b KO in Drd1a specific cells was sufficient to reproduce the immobility phenotype in TST. Intrastriatal injections of dopamine receptor, D1, agonist (SKF38393) and antagonist (SCH23390) revealed an additive immobility effect of Pde1b KO and dopamine receptor antagonism. The D1 agonist reversed the genotype immobility phenotype. The results suggest that reduction of PDE1B causes resistance to acute stress-induced depression-like behaviors through the dopamine pathways.
Committee
Charles Vorhees, Ph.D. (Committee Chair)
Steve Danzer, Ph.D. (Committee Member)
James Herman, Ph.D. (Committee Member)
Renu Sah, Ph.D. (Committee Member)
Rolf Stottman, Ph.D. (Committee Member)
Michael Williams, Ph.D. (Committee Member)
Pages
169 p.
Subject Headings
Neurology
Keywords
Phosphodiesterase
;
depression
;
tail suspension test
;
forced swim test
;
dopamine
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Refworks
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Citations
Hufgard, J. R. (2017).
PDE1B KO Confers Resilience to Acute Stress-induced Depression-like Behavior
[Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1504803606103525
APA Style (7th edition)
Hufgard, Jillian.
PDE1B KO Confers Resilience to Acute Stress-induced Depression-like Behavior.
2017. University of Cincinnati, Doctoral dissertation.
OhioLINK Electronic Theses and Dissertations Center
, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1504803606103525.
MLA Style (8th edition)
Hufgard, Jillian. "PDE1B KO Confers Resilience to Acute Stress-induced Depression-like Behavior." Doctoral dissertation, University of Cincinnati, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1504803606103525
Chicago Manual of Style (17th edition)
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Document number:
ucin1504803606103525
Download Count:
339
Copyright Info
© 2017, all rights reserved.
This open access ETD is published by University of Cincinnati and OhioLINK.