Antidepressant-like effects of neurokinin receptor antagonists in the forced swim test in the rat

Abstract

Although a wide assortment of agents is currently available for the treatment of depression, this disorder remains poorly managed in a large proportion of patients. Traditional antidepressant treatments target the biogenic amine systems. However, a growing body of evidence is implicating the involvement of neuropeptides in depression, especially the neurokinin substance P. This study evaluated the effects of selective antagonists of the tachykinin NK1, NK2, and NK3 receptors in the forced swim test, a commonly used screen for antidepressants. Rats were given CP-96,345 (2S, 3S)-cis-2-(diphenylmethyl)-N-[(2-methoxyphenyl)-methyl]-1-azabicyclo[2.2.2]octan-3-amine, SR 48968 (S)-N-methyl-N[4-(4-acetylamino-4-phenylpiperidino)-2-(3,4-dichlorophenyl)-butyl]benzamide, or SR 142801 (S)-(N)-(1-(3-(1-benzoyl-3-(3,4-dichlorophenyl) piperidin-3-yl) propyl)-4-phenylpiperidin-4-yl)-N-methylacetamide, antagonists of the NK1, NK2, and NK3 receptors, respectively, at doses of 2.5, 5, and 10 mg/kg, intraperitoneally (i.p.). The time of immobility during the forced swim test was used as an indicator of antidepressant activity of the antagonists. All antagonists decreased immobility times. CP-96,345 and SR 142801 showed dose-related effects; SR 48968 had its maximum effect at 2.5 mg/kg. The magnitude of the effects of the neurokinin receptor antagonists was approximately the same as that of amitriptyline and desipramine, two traditional antidepressants, both given at 10 mg/kg, i.p. This study provides comparative data on the relative effectiveness of NK1, NK2, and NK3 receptor antagonists in this screen for antidepressant drug activity.

Fig. 1

Effect of administration of amitriptyline (10 mg/kg, n=9), desipramine (10 mg/kg, n=8), CP-96,456 (5 mg/kg, n=8), CP-96,344 (5 mg/kg, n=8), SR 48968 (5 mg/kg, n=8), SR 142801 (5 mg/kg, n=8), and lorazepam (0.5 mg/kg, n=8) on immobility time during the 5-min test session of the forced swim test (n=32 for control group). Data are expressed as mean±S.E.M. **P<0.01 compared to control group.

Fig. 2

Dose–response relationship of tachykinin receptor antagonists (2.5, 5, and 10 mg/kg) on time of immobility during the 5-min test session of the forced swim test: (A) NK₁ antagonist, CP-96,345; (B) NK₂ antagonist, SR 48968; (C) NK₃ antagonist, SR 142801. Data are expressed as mean±S.E.M. P values given are with respect to control.