On the mechanism of the antidepressant-like action of group II mGlu receptor antagonist, MGS0039.
BACKGROUND
Several studies have suggested that modulation of the glutamatergic system could be a new, efficient way to achieve antidepressant activity. Behavioral data showed that group II mGlu receptor antagonists (i.e., (1R, 2R, 3R, 5R, 6R)-2-amino-3-(3,4-dichlorobenzyloxy)-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (MGS0039) and (2S)-2-amino-2-[(1S,2S)-2-carboxycycloprop-1-yl]-3-(xan th-9-yl) propanoic acid (LY341495)) elicited antidepressant activity in several animal models of depression in rats and/or mice. Although the antidepressant-like activity of MGS0039 and LY341495 is well documented, the mechanism of the antidepressant action of these compounds is still not clear.


OBJECTIVE
The aim of the present study was to specify the role of the serotonergic system in the mechanism of the antidepressant-like activity of group II mGlu receptor ligands by using the tail suspension test (TST) in mice; the role of AMPA receptors was also investigated. Furthermore, the possible antidepressant-like action of MGS0039 using the olfactory bulbectomy (OB) model of depression in rats was investigated.


RESULTS
The results of the TST studies showed that antidepressant-like action of group II mGlu receptor antagonists does not depend on serotonergic system activation. However, the AMPA receptor seems to play a key role in the antidepressant-like action of these compounds. Moreover, we have shown that repeated administration of MGS0039 attenuated OB-related deficits, confirming antidepressant-like activity of the tested compound.


CONCLUSIONS
The results suggest that the blockade of group II mGlu receptors may be effective in the treatment of depression. Moreover, we have found that the mechanism of action of group II mGlu receptor antagonists differs from that of typical antidepressants, such as SSRIs.
Pałucha-Poniewiera
Agnieszka
A
Department of Neurobiology, Institute of Pharmacology Polish Academy of Sciences, Smętna 12, 31-343, Kraków, Poland. nfpaluch@cyf-kr.edu.pl
Wierońska
Joanna M
JM
Brański
Piotr
P
Stachowicz
Katarzyna
K
Chaki
Shigeyuki
S
Pilc
Andrzej
A
D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D001362:Avoidance Learning / Q000187:drug effects; D001522:Behavior, Animal / Q000187:drug effects*; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology*; D003863:Depression / Q000188:drug therapy* / Q000378:metabolism / Q000523:psychology; D003998:Dicarboxylic Acids / Q000494:pharmacology*; D004195:Disease Models, Animal; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D019417:Hindlimb Suspension; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D009830:Olfactory Bulb / Q000601:surgery; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors / Q000378:metabolism; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012701:Serotonin / Q000172:deficiency; D012702:Serotonin Antagonists / Q000494:pharmacology
C483757:2-amino-3-(3,4-dichlorobenzyloxy)-6-fluorobicyclo(3.1.0)hexane-2,6-dicarboxylic acid; D000928:Antidepressive Agents; D001643:Bridged Bicyclo Compounds; D003998:Dicarboxylic Acids; D018691:Excitatory Amino Acid Antagonists; D018091:Receptors, AMPA; D018094:Receptors, Metabotropic Glutamate; D012702:Serotonin Antagonists; D012701:Serotonin