Antidepressant-like activity of CGP 36742 and CGP 51176, selective GABAB receptor antagonists, in rodents.
OBJECTIVE
A crucial role for the GABAB receptor in depression was proposed several years ago, but there are limited data to support this proposition. Therefore we decided to investigate the antidepressant-like activity of the selective GABAB receptor antagonists CGP 36742 and CGP 51176, and a selective agonist CGP 44532 in models of depression in rats and mice.


METHODS
Effects of CGP 36742 and CGP 51176 as well as the agonist CGP 44532 were assessed in the forced swim test in mice. Both antagonists were also investigated in an olfactory bulbectomy (OB) model of depression in rats, while CGP 51176 was also investigated in the chronic mild stress (CMS) rat model of depression. The density of GABAB receptors in the mouse hippocampus after chronic administration of CGP 51176 was also investigated.


RESULTS
The GABAB receptor antagonists CGP 36742 and CGP 51176 exhibited antidepressant-like activity in the forced swim test in mice. The GABAB receptor agonist CGP 44532 was not effective in this test, however, it counteracted the antidepressant-like effects of CGP 51176. The antagonists CGP 36742 and CGP 51176 were effective in an OB model of depression in rats. CGP 51176 was also effective in the CMS rat model of depression. Administration of CGP 51176 increased the density of GABAB receptors in the mouse hippocampus.


CONCLUSIONS
These data suggest that selective GABAB receptor antagonists may be useful in treatment of depression, and support an important role for GABA-ergic transmission in this disorder.
Nowak
G
G
Institute of Pharmacology, Polish Academy of Sciences, Kraków, Poland.
Partyka
A
A
Pałucha
A
A
Szewczyk
B
B
Wierońska
J M
JM
Dybała
M
M
Metz
M
M
Librowski
T
T
Froestl
W
W
Papp
M
M
Pilc
A
A
D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D001362:Avoidance Learning / Q000187:drug effects; D001522:Behavior, Animal / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005106:Exploratory Behavior / Q000187:drug effects; D005247:Feeding Behavior / Q000187:drug effects; D058788:GABA-B Receptor Antagonists; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D007099:Imipramine / Q000494:pharmacology; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D009943:Organophosphorus Compounds / Q000494:pharmacology*; D010721:Phosphinic Acids / Q000494:pharmacology*; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D018080:Receptors, GABA-B / Q000378:metabolism; D013315:Stress, Psychological / Q000503:physiopathology; D013395:Sucrose / Q000008:administration & dosage / Q000494:pharmacology; D013550:Swimming; D014316:Tritium
C516672:3-amino-2-hydroxypropylcyclohexylmethylphosphinic acid; D000928:Antidepressive Agents; D058788:GABA-B Receptor Antagonists; D009943:Organophosphorus Compounds; D010721:Phosphinic Acids; D018080:Receptors, GABA-B; D014316:Tritium; C079148:(3-aminopropyl)(n-butyl)phosphinic acid; D013395:Sucrose; D007099:Imipramine