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Research ArticleNEUROPHARMACOLOGY

Pharmacological Effects of the Metabotropic Glutamate Receptor 1 Antagonist Compared with Those of the Metabotropic Glutamate Receptor 5 Antagonist and Metabotropic Glutamate Receptor 2/3 Agonist in Rodents: Detailed Investigations with a Selective Allosteric Metabotropic Glutamate Receptor 1 Antagonist, FTIDC [4-[1-(2-Fluoropyridine-3-yl)-5-methyl-1H-1,2,3-triazol-4-yl]-N-isopropyl-N-methyl-3,6-dihydropyridine-1(2H)-carboxamide]

Akio Satow, Shunsuke Maehara, Satoko Ise, Hirohiko Hikichi, Miyuki Fukushima, Gentaroh Suzuki, Toshifumi Kimura, Takeshi Tanaka, Satoru Ito, Hiroshi Kawamoto and Hisashi Ohta
Journal of Pharmacology and Experimental Therapeutics August 2008, 326 (2) 577-586; DOI: https://doi.org/10.1124/jpet.108.138107
Akio Satow
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Shunsuke Maehara
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Satoko Ise
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Hirohiko Hikichi
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Miyuki Fukushima
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Gentaroh Suzuki
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Toshifumi Kimura
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Takeshi Tanaka
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Satoru Ito
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Hiroshi Kawamoto
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Hisashi Ohta
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Abstract

The functional roles of metabotropic glutamate receptor (mGluR) 1 in integrative brain functions were investigated using a potent and selective mGluR1 allosteric antagonist, FTIDC [4-[1-(2-fluoropyridine-3-yl)-5-methyl-1H-1,2,3-triazol-4-yl]-N-isopropyl-N-methyl-3,6-dihydropyridine-1(2H)-carboxamide], in comparison with the mGluR5 allosteric antagonist and the mGluR2/3 orthosteric agonist in rodents. FTIDC reduced maternal separation-induced ultrasonic vocalization and stress-induced hyperthermia without affecting behaviors in the elevated plus maze. An mGluR5 antagonist, 2-methyl-6-(phenylethynyl)-pyridine (MPEP), and an mGluR2/3 agonist, LY379268 [(1R,4R,5S,6R)-4-amino-2-oxabicyclo[3.1.0]hexane-4,6-dicarboxylic acid], showed anxiolytic activities in these models, suggesting involvement of postsynaptic mGluR1 in stress-related responses comparable with mGluR5 and mGluR2/3. Analgesic effects of FTIDC were seen in the formalin test but not in the tail immersion test. FTIDC selectively blocked methamphetamine-induced hyperlocomotion and disruption of prepulse inhibition, whereas MPEP and LY379268 did not alter those behaviors, suggesting that pharmacological blockade of mGluR1 could result in antipsychotic-like effects. FTIDC did not elicit catalepsy or impair motor functions at 10 times higher dose than doses showing antipsychotic-like action. In conclusion, blockade of mGluR1 showed antipsychotic-like effects without impairing motor functions, whereas blockade of mGluR5 and activation of mGluR2/3 did not display such activities.

Footnotes

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

  • doi:10.1124/jpet.108.138107.

  • ABBREVIATIONS: CNS, central nervous system; mGluR, metabotropic glutamate receptor; LY354740, (1S,2S,5R,6S)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylate monohydrate; LY379268, (1R,4R,5S,6R)-4-amino-2-oxabicyclo[3.1.0]hexane-4,6-dicarboxylic acid; iGluR, ionotropic glutamate receptor; NMDA, N-methyl-d-aspartate; MPEP, 2-methyl-6-(phenylethynyl)pyridine; JNJ16259685, (3,4-dihydro-2H-pyrano[2,3-b]quinolin-7-yl)(cis-4-methoxycyclohexyl)methanone; BAY 36-7620, (3aS,6aS)-6a-naphtalan-2-ylmethyl-5-methyliden-hexahydro-cyclopenta[c]furan-1-one; YM-230888, N-cycloheptyl-6-({[(2R)-tetrahydrofuran-2-ylmethyl]amino}methyl)thieno[2,3-d]pyrimidin-4-amine; EMQMCM, (3-ethyl-2-methyl-quinolin-6-yl)(4-methoxy-cyclohexyl)methanone methanesulfonate; FTIDC, 4-[1-(2-fluoropyridine-3-yl)-5-methyl-1H-1,2,3-triazol-4-yl]-N-isopropyl-N-methyl-3,6-dihydropyridine-1(2H)-carboxamide; DHPG, 3,5-dihydroxyphenylglycine; MAP, methamphetamine; SIH, stress-induced hyperthermia; PPI, prepulse inhibition; CPCCOEt, 7-(hydroxyimino)cyclopropan[b]chromen-1a-carboxylic acid ethyl ester; MK-801, (5S,10R)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate; USV, ultrasonic vocalization.

  • ↵ Embedded Image The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.

    • Received February 18, 2008.
    • Accepted May 16, 2008.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 326 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 326, Issue 2
1 Aug 2008
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Pharmacological Effects of the Metabotropic Glutamate Receptor 1 Antagonist Compared with Those of the Metabotropic Glutamate Receptor 5 Antagonist and Metabotropic Glutamate Receptor 2/3 Agonist in Rodents: Detailed Investigations with a Selective Allos…
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Research ArticleNEUROPHARMACOLOGY

Pharmacological Effects of the Metabotropic Glutamate Receptor 1 Antagonist Compared with Those of the Metabotropic Glutamate Receptor 5 Antagonist and Metabotropic Glutamate Receptor 2/3 Agonist in Rodents: Detailed Investigations with a Selective Allosteric Metabotropic Glutamate Receptor 1 Antagonist, FTIDC [4-[1-(2-Fluoropyridine-3-yl)-5-methyl-1H-1,2,3-triazol-4-yl]-N-isopropyl-N-methyl-3,6-dihydropyridine-1(2H)-carboxamide]

Akio Satow, Shunsuke Maehara, Satoko Ise, Hirohiko Hikichi, Miyuki Fukushima, Gentaroh Suzuki, Toshifumi Kimura, Takeshi Tanaka, Satoru Ito, Hiroshi Kawamoto and Hisashi Ohta
Journal of Pharmacology and Experimental Therapeutics August 1, 2008, 326 (2) 577-586; DOI: https://doi.org/10.1124/jpet.108.138107

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Research ArticleNEUROPHARMACOLOGY

Pharmacological Effects of the Metabotropic Glutamate Receptor 1 Antagonist Compared with Those of the Metabotropic Glutamate Receptor 5 Antagonist and Metabotropic Glutamate Receptor 2/3 Agonist in Rodents: Detailed Investigations with a Selective Allosteric Metabotropic Glutamate Receptor 1 Antagonist, FTIDC [4-[1-(2-Fluoropyridine-3-yl)-5-methyl-1H-1,2,3-triazol-4-yl]-N-isopropyl-N-methyl-3,6-dihydropyridine-1(2H)-carboxamide]

Akio Satow, Shunsuke Maehara, Satoko Ise, Hirohiko Hikichi, Miyuki Fukushima, Gentaroh Suzuki, Toshifumi Kimura, Takeshi Tanaka, Satoru Ito, Hiroshi Kawamoto and Hisashi Ohta
Journal of Pharmacology and Experimental Therapeutics August 1, 2008, 326 (2) 577-586; DOI: https://doi.org/10.1124/jpet.108.138107
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