Research reportDrug-induced suppression of ACTH secretion does not promote anti-depressive or anxiolytic effects

- We further studied the involvement of CRH and vasopressin in depression.
- Simultaneous treatment with CRHR1 and V1b antagonists suppress ACTH secretion (AST).
- Elevated plus maze, forced swimming and social interaction was studied in AST.
- Behavioral results point toward an anti-depressive profile similar to that seen by others.
- Antidepressive action was not greater than that of single drug treatments.

Mammals respond to a real or perceived stress in an integrated physiological and psychological fashion. Psychiatric disorders like major depression and anxiety have been associated to stressful events. In a previous study we demonstrated that the stress-induced ACTH secretion can be robustly inhibited by the concurrent use of CRF1 (CP154,526 - Pfizer) and V1B (SSR149415 - Sanofi-Aventis) non-peptide antagonists. A proof of mechanism was offered by substituting CP154,526 by SSR125543 and obtaining the same results on three stress models: forced swimming, ether vapor inhalation and restraint. SSR125543 effectively blocked only restraint stress-induced ACTH secretion. We then challenged the hypothesis that the concurrent use of both antagonists would have a potent effect on behavioral models of anxiety and depression. Decreasing doses (30-0.1 mg/kg s.c.) of both drugs were tested in three behavioral models: Porsolt forced swimming test, elevated plus maze and social interaction. Results showed that these drugs had no effect on anxiety models (plus maze and social interaction) but significantly reduced immobility time in the forced swimming test, suggesting anti-depressive action in a dose-range from 1 to 30 mg/kg, not different from the reported in the literature referring to one drug or the other. This negates the proposed hypothesis of summation/potentiation of effects as observed in stress-induced ACTH secretion. These results point toward the involvement of extra-hypothalamic sites for the anti-depressive effects. Recent Phase II clinical research on anti-depressive effects of these drugs has failed rising strong criticisms against the predictive value of behavioral tests currently employed.