An mGluR2/3 antagonist, MGS0039, exerts antidepressant and anxiolytic effects in behavioral models in rats.
BACKGROUND
Abnormalities of glutamatergic neurotransmission have been reportedly observed in psychiatric disorders. Previously, we demonstrated that (1R, 2R, 3R, 5R, 6R)-2-Amino-3-(3,4-dichlorobenzyloxy)-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (MGS0039) is a selective antagonist for group II metabotropic glutamate receptors (mGluR2/3), and that it exerted antidepressant effects in some animal behavioral tests.


OBJECTIVE
In the present study, we provide additional evidence that MGS0039 exhibits antidepressant and anxiolytic effects in experimental rodent models, which are predictive of clinical efficacy.


METHODS
The learned helplessness (LH) paradigm, which is a common model used to examine the depressive state, was used to assess antidepressant effects of MGS0039. Moreover, anxiolytic effects of MGS0039 were investigated in the conditioned fear stress (CFS) model, which represents emotional abnormality, including anxiety.


RESULTS
Intraperitoneal administration of MGS0039 (10 mg/kg) to rats for 7 days elicited a significant reduction in escape failures in the LH paradigm. In addition, rats treated with MGS0039 (2 mg/kg) showed significantly attenuated freezing behavior in a CFS model, indicating the anxiolytic-like potential of MGS0039.


CONCLUSIONS
These results suggest that the blockade of mGluR2/3 with MGS0039 may be effective in the treatment of depressive and anxiety disorders.
Yoshimizu
Takao
T
Psychiatric Diseases and Pain Research, Medicinal Pharmacology Laboratory, Taisho Pharmaceutical Co., Ltd., 1-403 Yoshino-cho, Kita-ku, Saitama, Saitama 331-9530, Japan.
Shimazaki
Toshiharu
T
Ito
Akie
A
Chaki
Shigeyuki
S
D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D000928:Antidepressive Agents / Q000494:pharmacology*; D001362:Avoidance Learning / Q000187:drug effects; D001522:Behavior, Animal / Q000187:drug effects*; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology*; D003214:Conditioning, Classical / Q000187:drug effects; D003998:Dicarboxylic Acids / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D008297:Male; D023421:Models, Animal; D009043:Motor Activity / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors*
C483757:2-amino-3-(3,4-dichlorobenzyloxy)-6-fluorobicyclo(3.1.0)hexane-2,6-dicarboxylic acid; D014151:Anti-Anxiety Agents; D000928:Antidepressive Agents; D001643:Bridged Bicyclo Compounds; D003998:Dicarboxylic Acids; D018094:Receptors, Metabotropic Glutamate; C108822:metabotropic glutamate receptor 2; C102718:metabotropic glutamate receptor 3