The NK1-receptor antagonist NKP608 has an antidepressant-like effect in the chronic mild stress model of depression in rats

The chronic mild stress (CMS) model of depression was used to study the pot ential antidepressant-like activity of NKP608, a non-peptidic, specific, po tent and orally active NK1 receptor antagonist. In this model, a substantia l decrease in consumption of a 1% sucrose solution is observed in rats cont inously subjected to a variety of mild stressors. This effect can be revers ed by chronic administration of various classes of antidepressant drugs. Ch ronic, oral treatment with NKP608 (once daily for 5 weeks) gradually revers ed CMS-induced reductions in sucrose consumption and, the magnitude of this effect was comparable to that observed following administration of imipram ine (10 mg/kg). The time-course of action of NKP608 in the CMS model was do se-dependent. At the dose of 0.03 mg/kg, NKP608 caused a full reversal of t he CMS-induced deficit in sucrose consumption after 4 weeks of treatment (c omparable to 5 weeks required for imipramine), while only I week of treatme nt was required in the group receiving the dose of 0.1 mg/kg NKP608. Lower (0.003 mg/kg) and higher (1.0 mg/kg) doses of the compound were ineffective . These results suggest that NKP608 has antidepressant-like properties in t he CMS model in rats; the effect was comparable to conventional drugs, but the onset of action was faster than with the representative tricyclic antid epressant imipramine. (C) 2000 Elsevier Science B.V. All rights reserved.