Repeated antidepressant therapy increases cyclic GMP signaling in rat hippocampus

Abstract

Cyclic adenosine monophosphpate (cAMP) signaling is thought to be involved in the pathophysiology of major depressive disorder and antidepressant action; however, relatively little is known about the possible role of cyclic guanosine monophosphate (cGMP) signaling. Accumulating evidence suggests that crosstalk occurs between cAMP and cGMP pathways. There is a need to clarify the trajectory of cAMP and cGMP concentrations, their synthesis by cyclases, and degradation by phosphodiesterases (PDEs) to understand the role of cyclic mononucleotide signaling in the effect of chronic antidepressant therapy. We used quantitative real-time PCR and enzyme immunoassay to systematically investigate the expression of intracellular signaling cascade elements in the hippocampus of rats chronically treated with the antidepressants fluoxetine and amitriptyline. We found increased cGMP levels, which were consistent with our findings of decreased PDE gene expression. Immunoassay results showed unchanged cAMP levels. We conclude that increased cGMP signaling might underlie the efficacy of chronic antidepressant treatment.

Fig. 1

Effect of chronic fluoxetine (FLX) and amitriptyline (AMI) treatment on PDE and cyclase gene expression in the rat hippocampus. Results are expressed as mean + s.e.m. for FLX and AMI as percentage of saline-treated control (SAL) (n=9–10 animals/group). Asterisks indicate significant differences versus SAL (* p<0.05, ** p<0.01, *** p<0.001 one-way analysis of variance with Neuman-Keuls post hoc analyses).

Fig. 2

Mean + s.e.m. concentrations of cAMP (Fig. 2a) and cGMP (Fig. 2b) (expressed as pmol/mL) in the hippocampus of rats treated chronically with saline (SAL), fluoxetine (FLX) and amitriptyline (AMI) (n=9–10 animals/group). Asterisks indicate significant differences versus SAL (** p<0.01 one-way analysis of variance with Neuman-Keuls post- hoc analyses).