title: Acute and sustained effects of a metabotropic glutamate 5 receptor antagonist in the novelty-suppressed feeding test.
abstract: Accumulated evidence indicates that metabotropic glutamate 5 (mGlu5) receptor blockade exerts antidepressant-like and anxiolytic-like effects in several animal models. The novelty-suppressed feeding (NSF) test is used to measure anxiety-induced hypophagia in rodents. Anxiogenic-like behavior can be counteracted by acute treatment with anxiolytics or chronic treatment with antidepressants. The objective of the present study was to investigate the effect of an mGlu5 receptor antagonist, 2-methyl-6-(phenylethynyl)-pyridine (MPEP), using the NSF test and to investigate the mechanisms underlying the effects of MPEP. The administration of MPEP at 1 h prior to testing significantly shortened the latency period until feed (an acute effect), and this effect lasted for 24 h (a sustained effect), similar to the results observed using the N-methyl-D-aspartate receptor antagonist ketamine. Pretreatment with a protein synthesis inhibitor, anisomycin, blocked the sustained, but not the acute, effects of MPEP, suggesting the involvement of new protein synthesis in the sustained effect of MPEP. In addition, the sustained effect of MPEP in the NSF test was partially abolished by pretreatment with a mammalian target of rapamycin (mTOR) antagonist, rapamycin. In contrast, a tropomyosin-related kinase, the tyrosine kinase inhibitor K252a, did not counteract the sustained effects of MPEP in this test. Taken together, these results are the first report to demonstrate that the blockade of the mGlu5 receptor exerted acute and sustained effects in the NSF test and that new protein synthesis may contribute to the sustained effects of MPEP, which may not mediate brain-derived neurotrophic factor-mTOR signaling.
authors.affiliation: Discovery Pharmacology I, Molecular Function and Pharmacology Laboratories, Taisho Pharmaceutical Co., Ltd., 1-403 Yoshino-cho, Kita-ku, Saitama, Saitama 331-9530, Japan. m.iijima@po.rd.taisho.co.jp
authors.forename: Michihiko
authors.initials: M
authors.lastname: Iijima
authors.forename: Kenichi
authors.initials: K
authors.lastname: Fukumoto
authors.forename: Shigeyuki
authors.initials: S
authors.lastname: Chaki
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D014151:Anti-Anxiety Agents / Q000008:administration & dosage*; D001007:Anxiety / Q000175:diagnosis / Q000188:drug therapy*; D002227:Carbazoles / Q000008:administration & dosage; D003975:Diazepam / Q000627:therapeutic use; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D005106:Exploratory Behavior / Q000187:drug effects*; D005247:Feeding Behavior / Q000187:drug effects*; D016666:Fluvoxamine / Q000627:therapeutic use; D007166:Immunosuppressive Agents / Q000494:pharmacology; D026121:Indole Alkaloids / Q000008:administration & dosage; D007266:Inhibition, Psychological; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011725:Pyridines / Q000008:administration & dosage*; D011930:Reaction Time / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology; D013997:Time Factors
chemical_list: D014151:Anti-Anxiety Agents; D002227:Carbazoles; D004791:Enzyme Inhibitors; D007166:Immunosuppressive Agents; D026121:Indole Alkaloids; D011725:Pyridines; C121465:6-methyl-2-(phenylethynyl)pyridine; C049985:staurosporine aglycone; D016666:Fluvoxamine; D003975:Diazepam; D020123:Sirolimus