Antidepressant-like effects of the phosphodiesterase-4 inhibitor etazolate and phosphodiesterase-5 inhibitor sildenafil via cyclic AMP or cyclic GMP signaling in mice.
Inhibition of phosphodiesterase-4 or 5 (PDE4 or PDE5) increases cyclic adenosine monophosphate (cAMP)- or cyclic guanosine monophosphate (cGMP), respectively, which activates cAMP response element-binding protein (CREB)/brain-derived neurotrophic factor (BDNF)/neuropeptide VGF (non-acryonimic) signaling and produces antidepressant-like effects on behavior. However, causal links among these actions have not been established. In the present study, mice were evaluated for the effects of etazolate and sildenafil, the inhibitor of PDE4 or PDE5, respectively, on depressive-like behavior induced by chronic unpredictable mild stress (CUMS) in the forced-swimming test (FST) and tail suspension test (TST), in the presence or absence of the inhibitor of protein kinase A (PKA) or protein kinase G (PKG) via intracerebroventricular (i.c.v.) infusions. The levels of cAMP, cGMP and expression of pCREB, CREB, BDNF and VGF in both the hippocampus and prefrontal cortex were determined. The results showed that etazolate at 5.0 mg/kg or sildenafil at 30 mg/kg significantly reversed CUMS-induced depressive-like behavior; the effects were paralleled with the increased levels of cAMP/pCREB/BDNF/VGF or cGMP/pCREB/BDNF/VGF signaling, respectively. These effects were completely abolished following inhibition of PKA or PKG, respectively. The results suggest that inhibition of PDE4 by etazolate or PDE5 by sildenafil produced antidepressant-like effects in CUMS-treated animals via cAMP or cGMP signaling, which shares the common downstream signal pathway of CREB/BDNF/VGF.
Department of Pharmacology, Ningbo University School of Medicine, 818 Fenghua Road, Ningbo, Zhejiang, 315211, People's Republic of China, wangchuang@nbu.edu.cn.
Chuang
C
Wang
Jianrui
J
Zhang
Yang
Y
Lu
Peipei
P
Lin
Tonghe
T
Pan
Xin
X
Zhao
Aiming
A
Liu
Qinwen
Q
Wang
Wenhua
W
Zhou
Han-Ting
HT
Zhang
D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001522:Behavior, Animal / Q000187:drug effects*; D000242:Cyclic AMP / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D003863:Depression / Q000188:drug therapy / Q000378:metabolism; D004974:Etazolate / Q000494:pharmacology* / Q000627:therapeutic use; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D010879:Piperazines / Q000494:pharmacology* / Q000627:therapeutic use; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism; D011687:Purines / Q000494:pharmacology / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects*; D000068677:Sildenafil Citrate; D013449:Sulfonamides / Q000494:pharmacology* / Q000627:therapeutic use; D013550:Swimming
D000928:Antidepressive Agents; D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D013449:Sulfonamides; D000068677:Sildenafil Citrate; D000242:Cyclic AMP; D006152:Cyclic GMP; D004974:Etazolate