Blockade of CRF(1) or V(1b) receptors reverses stress-induced suppression of neurogenesis in a mouse model of depression.
Repeated exposure to stress is known to induce structural remodelling and reduction of neurogenesis in the dentate gyrus. Corticotrophin-releasing factor (CRF) and vasopressin (AVP) are key regulators of the stress response via activation of CRF(1) and V(1b) receptors, respectively. The blockade of these receptors has been proposed as an innovative approach for the treatment of affective disorders. The present study aimed at determining whether the CRF(1) receptor antagonist SSR125543A, the V(1b) receptor antagonist SSR149415, and the clinically effective antidepressant fluoxetine may influence newborn cell proliferation and differentiation in the dentate gyrus of mice subjected to the chronic mild stress (CMS) procedure, a model of depression with predictive validity. Repeated administration of SSR125543A (30 mg/kg i.p.), SSR149415 (30 mg/kg i.p.), and fluoxetine (10 mg/kg i.p.) for 28 days, starting 3 weeks after the beginning of the stress procedure, significantly reversed the reduction of cell proliferation produced by CMS, an effect which was paralleled by a marked improvement of the physical state of the coat of stressed mice. Moreover, mice subjected to stress exhibited a 53% reduction of granule cell neurogenesis 30 days after the end of the 7-week stress period, an effect which was prevented by all drug treatments. Collectively, these results point to an important role of CRF and AVP in the regulation of dentate neurogenesis, and suggest that CRF(1) and V(1b) receptor antagonists may affect plasticity changes in the hippocampal formation, as do clinically effective antidepressants.
Alonso
R
R
Sanofi-Synthelabo Recherche, Rue du Professeur J. Blayac, Montpellier, France. richard.alonso@sanofi-synthelabo.com
Griebel
G
G
Pavone
G
G
Stemmelin
J
J
Le Fur
G
G
Soubrié
P
P
D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology; D065092:Antidiuretic Hormone Receptor Antagonists; D003863:Depression / Q000503:physiopathology* / Q000517:prevention & control; D004195:Disease Models, Animal; D005473:Fluoxetine / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009474:Neurons / Q000166:cytology* / Q000187:drug effects; D011759:Pyrrolidines / Q000494:pharmacology*; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors*; D013315:Stress, Psychological / Q000517:prevention & control*; D013844:Thiazoles / Q000494:pharmacology*
C456029:1-(5-chloro-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl)-4-hydroxy-N,N-dimethyl-2-pyrrolidinecarboxamide; C451725:4-(2-chloro-4-methoxy-5-methylphenyl)-N(2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)-5-methyl-N-(2-propynyl)-1,3-thiazol-2-amine; D000928:Antidepressive Agents; D065092:Antidiuretic Hormone Receptor Antagonists; D007211:Indoles; D011759:Pyrrolidines; D018019:Receptors, Corticotropin-Releasing Hormone; D013844:Thiazoles; D005473:Fluoxetine