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

Abstract

Rationale: 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.

Objectives: 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.

Fig. 1

Structures of antalarmin (a), LWH234 (b), CP154,526 (c), and R121919 (d)

Fig. 2

The effects of desipramine (a), fluoxetine (b), antalarmin (c), LWH234 (d), CP154,526 (e), and R121919 (e) in the forced swim test in rats. Rats were administered sub-chronic injections of vehicle or a single dose of either drug 23.5, 5, and 1 h prior to day 2 swim test (N=6–8 per dose). The bars and vertical lines above each bar represent the mean and standard error of the mean (SEM) for immobility (open bars), swimming (single-hatched bars), and climbing counts (double-hatched bars). *p<0.05, **p<0.01

Fig. 3

The effects of desipramine (DMI) (a), and fluoxetine (FLX) (b), antalarmin (c), LWH234 (LWH) (d), CP154,526 (CP) (e), and R121919 (R12) (f) on swim-induced increase in ACTH. Blood samples were taken before (pre d1) and after (post d1) day 1 swim and before (pre d2) and after (post d2) day 2 swim. **p<0.01

Fig. 4

The effects of LWH234 on restraint-induced increases in ACTH. Baseline bloods were collected before drug injection, and LWH234 was injected 60 min prior to restraint initiation. Blood samples were collected immediately after restraint (15 min) and 30, 60, and 90 min following restraint termination