Comparison of the V1b antagonist, SSR149415, and the CRF1 antagonist, CP-154,526, in rodent models of anxiety and depression.
Vasopressin and corticotropin releasing factor (CRF) are both critical regulators of an animal's stress response and have been linked to anxiety and depression. As such, antagonists of the CRF1 and V1b receptor subtypes are being developed as potential treatments for affective disorders. The two most characterized V1b and CRF1 antagonists are SSR149415 and CP-154,526, respectively, and the present studies were designed to compare these two compounds in acute animal models of affective disorders. We employed five anxiety models: Separation-induced pup vocalizations (guinea pig and rat), elevated plus-maze (EPM), conditioned lick suppression (CLS), and marble burying (mouse); as well as three depression models: forced swim test (FST; mouse and rat) and tail suspension test (TST; mouse). SSR149415 (1-30 mg/kg) was active in the vocalization, EPM and CLS models, but inactive in marble burying. CP-154,526 (1-30 mg/kg) was active in vocalization models, but inactive in EPM, CLS, and marble burying. SSR149415 was inactive in all depression models; CP-154,526 was active in rat FST but inactive in mouse models. This work demonstrates the different profiles of V1b and CRF1 receptor antagonists and supports both approaches in the treatment of affective disorders.
Hodgson
R A
RA
Department of Neurobiology, Schering Plough Research Institute, Kenilworth, NJ 07033, USA. robert.hodgson@spcorp.com
Higgins
G A
GA
Guthrie
D H
DH
Lu
S X
SX
Pond
A J
AJ
Mullins
D E
DE
Guzzi
M F
MF
Parker
E M
EM
Varty
G B
GB
D000818:Animals; D065092:Antidiuretic Hormone Receptor Antagonists; D001007:Anxiety / Q000188:drug therapy* / Q000378:metabolism / Q000523:psychology; D003213:Conditioning, Psychological / Q000187:drug effects; D003863:Depression / Q000188:drug therapy* / Q000378:metabolism / Q000523:psychology; D005260:Female; D006168:Guinea Pigs; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D011743:Pyrimidines / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology*; D011759:Pyrrolidines / Q000494:pharmacology*; D051381:Rats; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017483:Receptors, Vasopressin / Q000378:metabolism; D014828:Vocalization, Animal / Q000187:drug effects; D000099052:CRF Receptor, Type 1
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; D065092:Antidiuretic Hormone Receptor Antagonists; C101628:CP 154526; D007211:Indoles; D011743:Pyrimidines; D011758:Pyrroles; D011759:Pyrrolidines; D018019:Receptors, Corticotropin-Releasing Hormone; D017483:Receptors, Vasopressin; D000099052:CRF Receptor, Type 1