Abstract |
Major depressive disorder is a common, but serious, psychiatric dysfunction that affects 21% of the population worldwide. Rolipram, a first-generation phosphodiesterase-4 ( PDE4) inhibitor, has been shown to have significant antidepressant and cognitive enhancement effects; however, it was unsuccessful in clinic trials because of PDE4-dependent side effects such as nausea and emesis. In this study, we investigated the neuropharmacology of the novel PDE4 inhibitor chlorbipram and the classical PDE4 inhibitor rolipram. Using antidepressant-sensitive behavioral tests, we demonstrated that the acute single administration of chlorbipram (0.075-0.6 mg/kg) produced antidepressant-like effects, as evidenced by decreases in the duration of immobility in Kunming mice in the forced swim and tail suspension tests, and no significant changes in locomotor activity. Scopolamine-induced cognitive dysfunction was also significantly attenuated in the Morris water maze test after the treatment of Sprague Dawley rats with different doses of chlorbipram (0.5-1.5mg/kg). Furthermore, we evaluated the emetic potential of chlorbipram in beagle dogs. After oral administration, 0.5mg/kg rolipram showed emetic profiles in all dogs within 20 minutes, whereas chlorbipram did not induce any emesis during the 120-min observation period, even at the 1.0mg/kg dose. Together, our data suggest that chlorbipram is a novel antidepressant and cognitive enhancer with little or no emetic potency.
|
Authors | Ming-Zi Zhang, Zhong-Zhen Zhou, Xin Yuan, Yu-Fang Cheng, Bing-Tian Bi, Mei-Fang Gong, Yu-Pin Chen, Jiang-Ping Xu |
Journal | European journal of pharmacology
(Eur J Pharmacol)
Vol. 721
Issue 1-3
Pg. 56-63
(Dec 05 2013)
ISSN: 1879-0712 [Electronic] Netherlands |
PMID | 24113523
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
|
Copyright | © 2013 Elsevier B.V. All rights reserved. |
Chemical References |
- Antidepressive Agents
- Phosphodiesterase 4 Inhibitors
- Pyridazines
- chlorbipram
- pyridazine
- Cyclic Nucleotide Phosphodiesterases, Type 4
|
Topics |
- Animals
- Antidepressive Agents
(adverse effects, pharmacology)
- Behavior, Animal
(drug effects)
- Cognition
(drug effects)
- Cyclic Nucleotide Phosphodiesterases, Type 4
(metabolism)
- Dogs
- Female
- Male
- Mice
- Phosphodiesterase 4 Inhibitors
(adverse effects, pharmacology)
- Pyridazines
(adverse effects, pharmacology)
- Rats
- Safety
- Vomiting
(chemically induced)
|