Antidepressant-like action of AGN 2979, a tryptophan hydroxylase activation inhibitor, in a chronic mild stress model of depression in rats

Chronic mild stress (CMS) procedure was used to study an anti depressant-like activity of AGN 2979, a selective inhibitor of tryptophan hydroxylase (TH) activation. At the dose of 4 mg/kg, AGN 2979 fully reversed the CMS-induced reduction in the consumption of 1% sucrose solution. This effect was maintained for at least I week after cessation of treatment and no signs of withdrawal were observed in either stressed or control animals receiving AGN 2979. The lower (1 mg/kg) and higher (16 mg/kg) doses were ineffective. The magnitude of action of AGN 2979 in the CMS model was comparable to that of imipramine ( 10 mg/kg) but its onset of action appears to be faster since the inhibition of sucrose intake in stressed animals was already reversed after the 1st week of AGN 2979 administration while imipramine required 3 weeks of treatment to cause similar effect. These results provide support for the hypothesis that inhibition of TH activation may result in a potent antidepressant activity. (C) 2001 Elsevier Science B.V. All rights reserved.