The effects of CRF antagonists, antalarmin, CP154,526, LWH234, and R121919, in the forced swim test and on swim-induced increases in adrenocorticotropin in rats.
BACKGROUND
Exposure to extreme stress has been suggested to produce long-term, detrimental alterations in the hypothalamic-pituitary-adrenal (HPA) axis leading to the development of mental disorders such as depression. Therefore, compounds that block the effects of stress hormones were investigated as potential therapeutics for depression.


OBJECTIVE
In the present study, we compared the potential antidepressant-like effects of four CRF antagonists, antalarmin, CP154,526, R121919, and LWH234 (at 3, 10, and 30 mg/kg i.p., 60 min prior to the forced swim test) and the corresponding effect on swim-induced HPA activation to better elucidate the relation between HPA activity and antidepressant activity.


METHODS
The antidepressant-like effects of the CRF antagonists and known antidepressants were determined in the rat forced swim test, and blood samples were obtained before and after swimming for the evaluation of adrenocorticotropin-releasing hormone (ACTH) levels.


RESULTS
Antalarmin, CP154,526, and R121919 did not produce antidepressant-like effects in the forced swim test although these compounds decreased swim-induced increases in ACTH to various extents. In contrast, LWH234 reduced immobility in the forced swim test, without altering the swim-stress-induced ACTH response. However, this compound antagonized restraint-induced ACTH release.


CONCLUSIONS
These data suggest that reducing stress-induced increases in HPA activity alone may not be sufficient to produce antidepressant-like activity; however, reductions in HPA activity may contribute to antidepressant actions of some treatments. In addition, it is proposed that CRF antagonists may alter differentially the HPA axis depending on the type of stressor used or behavioral measure evaluated.
Jutkiewicz
Emily M
EM
Department of Pharmacology, University of Michigan Medical School, 1301 MSRB 3, Ann Arbor, MI 48109-0632, USA. ejutkiew@umich.edu
Wood
Susan K
SK
Houshyar
Hani
H
Hsin
Ling-Wei
LW
Rice
Kenner C
KC
Woods
James H
JH
D000324:Adrenocorticotropic Hormone / Q000097:blood*; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D003346:Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors*; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects; D008297:Male; D010913:Pituitary-Adrenal System / Q000187:drug effects; D011743:Pyrimidines / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012149:Restraint, Physical; D013315:Stress, Psychological / Q000097:blood*; D013550:Swimming; D014230:Triazoles / Q000494:pharmacology*
D000928:Antidepressive Agents; C101628:CP 154526; C505865:LWH234; D011743:Pyrimidines; D011758:Pyrroles; C412383:R 121919; D014230:Triazoles; C103016:antalarmin; D000324:Adrenocorticotropic Hormone; D003346:Corticotropin-Releasing Hormone