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NEUROPHARMACOLOGY

Efficacy of the MCHR1 Antagonist N-[3-(1-{[4-(3,4-Difluorophenoxy)phenyl]methyl}(4-piperidyl))-4-methylphenyl]-2-methylpropanamide (SNAP 94847) in Mouse Models of Anxiety and Depression following Acute and Chronic Administration Is Independent of Hippocampal Neurogenesis

Center for Neurobiology and Behavior, Columbia University, New York, New York (D.J.D., K.C.K., K.A.H., M.D.S., I.M., R.H.); EA3544 Laboratoire de Neuropharmacologie, Faculté de Pharmacie, Châtenay-Malabry, France (D.J.D.); Roche Palo Alto LLC, Palo Alto, California (L.S.); and Lundbeck Research USA, Paramus, New Jersey (D.A.C., H.Z., C.J.S., L.G.H., X.I.P., D.D., M.R.M., C.P.G.)

Melanin-concentrating hormone (MCH) is a hypothalamic neuropeptide that plays a role in the modulation of food intake and mood. In rodents, the actions of MCH are mediated via the MCHR1 receptor. The goal of this study was to investigate the effects of acute (1 h) and chronic (28 days) p.o. dosing of a novel MCHR1 antagonist, N-[3-(1-{[4-(3,4-difluorophenoxy)-phenyl]methyl}(4-piperidyl))-4-methylphenyl]-2-methylpropanamide (SNAP 94847), in three mouse models predictive of antidepressant/anxiolytic-like activity: novelty suppressed feeding (NSF) in 129S6/SvEvTac mice and light/dark paradigm (L/D) and forced swim test (FST) in BALB/cJ mice. A significant increase in the time spent in the light compartment of the L/D box was observed in response to acute and chronic treatment with SNAP 94847. An anxiolytic/antidepressant-like effect was found in the NSF test after acute and chronic treatment, whereas no effect was observed in the FST. Because neurogenesis in the dentate gyrus has been shown to be a requirement for the effects of antidepressants in the NSF test, we investigated whether neurogenesis was required for the effect of SNAP 94847. We showed that chronic treatment with SNAP 94847 stimulated proliferation of progenitors in the dentate gyrus. The efficacy of SNAP 94847 in the NSF test, however, was unaltered in mice in which neurogenesis was suppressed by X-irradiation. These results indicate that SNAP 94847 has a unique anxiolytic-like profile after both acute and chronic administration and that its mechanism of action is distinct from that of selective serotonin reuptake inhibitors and tricyclic antidepressants.

Address correspondence to: René Hen, N.Y.S.P.I. Kolb Research Annex, Room 767, 1051 Riverside Drive, Unit 87, New York, NY 10032-2695. E-mail: rh95{at}columbia.edu

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