title: Serotonin-1A receptor stimulation mediates effects of a metabotropic glutamate 2/3 receptor antagonist, 2S-2-amino-2-(1S,2S-2-carboxycycloprop-1-yl)-3-(xanth-9-yl)propanoic acid (LY341495), and an N-methyl-D-aspartate receptor antagonist, ketamine, in the novelty-suppressed feeding test.
abstract: BACKGROUND
  α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor stimulation has been proposed to be a common neural mechanism of metabotropic glutamate 2/3 (mGlu2/3) receptor antagonists and an N-methyl-D-aspartate receptor antagonist, ketamine, exerting antidepressant effects in animal models. AMPA receptor stimulation has also been shown to mediate an increase in the extracellular level of serotonin (5-HT) in the medial prefrontal cortex by an mGlu2/3 receptor antagonist in rats. However, involvement of the serotonergic system in the actions of mGlu2/3 receptor antagonists and ketamine is not well understood.
  
  
  OBJECTIVE
  We investigated involvement of the serotonergic system in the effects of an mGlu2/3 receptor antagonist, 2S-2-amino-2-(1S,2S-2-carboxycycloprop-1-yl)-3-(xanth-9-yl)propanoic acid (LY341495), and ketamine in a novelty-suppressed feeding (NSF) test in mice.
  
  
  RESULTS
  The intraperitoneal administration of LY341495 or ketamine at 30 min prior to the test significantly shortened latency to feed, which was attenuated by an AMPA receptor antagonist, 2,3-dioxo-6-nitro-1,2,3,4-tetrahydr-obenzo[f]quinoxaline-7-sulfonamide (NBQX). The effects of LY341495 and ketamine were no longer observed in mice pretreated with a tryptophan hydroxylase inhibitor, para-chlorophenylalanine (PCPA). Moreover, the effects of LY341495 and ketamine were blocked by a 5-HT1A receptor antagonist, N-{2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl}-N-(2-pyridynyl) cyclohexane-carboxamide (WAY100635), but not by a 5-HT2A/2C receptor antagonist, ritanserin. Likewise, an AMPA receptor potentiator, 2,3-dihydro-1,4-benzodioxin-7-yl-(1-piperidyl)methanone (CX546), shortened latency to feed in the NSF test, which was prevented by depletion of 5-HT and blockade of 5-HT1A receptor.
  
  
  CONCLUSIONS
  These results suggest that AMPA receptor-dependent 5-HT release and subsequent 5-HT1A receptor stimulation may be involved in the actions of an mGlu2/3 receptor antagonist and ketamine in the NSF test.
authors.affiliation: Discovery Pharmacology І, Molecular Function and Pharmacology Laboratories, Taisho Pharmaceutical Co., Ltd., 1-403 Yoshino-cho, Kita-ku, Saitama, Saitama, 331-9530, Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Fukumoto
authors.forename: Michihiko
authors.initials: M
authors.lastname: Iijima
authors.forename: Shigeyuki
authors.initials: S
authors.lastname: Chaki
mesh_terms: D000596:Amino Acids / Q000494:pharmacology*; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D004149:Dioxoles / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D005247:Feeding Behavior / Q000187:drug effects* / Q000502:physiology; D010134:Fenclonine / Q000494:pharmacology; D007649:Ketamine / Q000494:pharmacology*; D008297:Male; D008810:Mice, Inbred C57BL; D009483:Neuropsychological Tests; D010879:Piperazines / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors / Q000378:metabolism; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000378:metabolism; D016713:Ritanserin / Q000494:pharmacology; D058829:Serotonin 5-HT1 Receptor Antagonists / Q000494:pharmacology; D058830:Serotonin 5-HT2 Receptor Antagonists / Q000494:pharmacology; D014365:Tryptophan Hydroxylase / Q000037:antagonists & inhibitors / Q000378:metabolism; D014966:Xanthenes / Q000494:pharmacology*
chemical_list: C443080:1-(1,4-benzodioxan-6-ylcarbonyl)piperidine; D000596:Amino Acids; D000928:Antidepressive Agents; D004149:Dioxoles; D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; C114624:LY 341495; D010879:Piperazines; D010880:Piperidines; D011725:Pyridines; D011810:Quinoxalines; D018091:Receptors, AMPA; D018094:Receptors, Metabotropic Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; D058829:Serotonin 5-HT1 Receptor Antagonists; D058830:Serotonin 5-HT2 Receptor Antagonists; D014966:Xanthenes; C108822:metabotropic glutamate receptor 2; C102718:metabotropic glutamate receptor 3; C062865:2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline; D016713:Ritanserin; D007649:Ketamine; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide; D014365:Tryptophan Hydroxylase; D010134:Fenclonine