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Publication Date

2010-03-02

Availability

UM campus only

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PHD)

Department

Neuroscience (Medicine)

Date of Defense

2010-02-05

First Committee Member

Philip McCabe

Second Committee Member

Vance Lemmon

Third Committee Member

Yossef Itzhak

Fourth Committee Member

Ma-Li Wong

Abstract

Cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) act as second messengers in intracellular signaling cascades to influence neuronal responses. Hippocampal cAMP signaling is thought to underlie the pathophysiology of major depressive disorder (MDD) and antidepressant action; however, little is known about the possible role of cGMP signaling. Furthermore, circadian rhythm disturbances can occur as part of the clinical symptoms of MDD and resolve with antidepressant therapy. The pineal gland is relevant to circadian rhythms as it secretes the hormone melatonin following activation of cAMP signaling and the rate-limiting enzyme for its synthesis, arylalkylamine N-acetyltransferase (AA-NAT). Little is known about the contribution of the phosphodiesterase (PDE) system to antidepressant-induced alterations in pineal cAMP signaling and melatonin synthesis. There is a need to clarify the trajectory of cAMP and cGMP concentrations, their synthesis by cyclases, and degradation by PDEs to understand the role of cyclic mononucleotide signaling in the effect of chronic antidepressant therapy. Using quantitative real-time PCR and enzyme immunoassay, we systematically studied elements of intracellular signaling in the hippocampus of rats chronically treated with imipramine, fluoxetine, and amitriptyline and in the pineal gland of rats treated chronically with fluoxetine. In the hippocampus, we found chronic imipramine downregulated cAMP signaling with decreased cAMP, increased PDEs and decreased adenylate cyclase mRNA. In contrast, repeated fluoxetine and amitriptyline increased hippocampal cGMP signaling, with increased cGMP and decreased PDE mRNA. We conclude that in contrast to the assumption of antidepressant-mediated increases in cAMP levels, increased hippocampal cGMP signaling might underlie the efficacy of chronic antidepressant treatment. A follow up study using cultured embryonic rat hippocampal cells in vitro treated with the PDE type 5 inhibitor, sildenafil, demonstrated increased cAMP content following acute and chronic treatment, indicating either crosstalk between cAMP and cGMP pathways or a non-specific inhibitory effect of sildenafil on other PDEs. In the pineal gland, we found elevated melatonin synthesis with increased pineal AA-NAT mRNA and daytime plasma melatonin and downregulated cAMP signaling with increased PDE and unchanged AC pineal mRNA, and decreased pineal cAMP. We conclude that chronic fluoxetine increases daytime plasma melatonin and pineal AA-NAT mRNA despite downregulated pineal cAMP signaling.

Keywords

Antidepressant; Phosphodiesterase; Hippocampus; Pineal Gland; Melatonin; Cyclic AMP; Cyclic GMP

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