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]

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 separationinduced 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 methamphetamineinduced 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.L-Glutamate is the major excitatory neurotransmitter in the mammalian central nervous system (CNS) and acts on ionotropic and metabotropic glutamate receptors (mGluRs). The mGluR family consists of eight receptor subtypes, which are divided into three groups based on sequence homology, pharmacological profiles, and signal transduction pathways (De Blasi et al., 2001;Spooren et al., 2003). Group I mGluRs comprise mGluR1 and mGluR5, which are coupled with G q to activate phospholipase C, leading to the release of intracelArticle, publication date, and citation information can be found at

Correlation of Receptor Occupancy of Metabotropic Glutamate Receptor Subtype 1 (mGluR1) in Mouse Brain With In Vivo Activity of Allosteric mGluR1 Antagonists

“…In the present study, the doses of FTIDC were correlated with receptor occupancy in the brain, and a dose of 30 mg/kg almost fully inhibited (S)-3,5-DHPGinduced face-washing behavior. In contrast, the doses of FTIDC in the present study neither decreased spontaneous locomotor activity nor impaired rotorod performance (20). These results suggested that motor deficit was not elicited in mice at least at doses of FTIDC that significantly occupied mGluR1 in the brain and antagonized S-(3,5)-DHPG-induced face washing behavior.…”

Metabotropic Glutamate Receptors: Potential Drug Targets for Psychiatric Disorders

“…In contrast, mGlu1 receptor antagonists neither induced catalepsy nor impaired rotarod performance [58,59], suggesting that mGlu1 receptor antagonists may not cause motor dysfunction, unlike the actions of typical antipsychotics. This atypical activity of mGlu1 receptor antagonists is further supported by c-fos induction, in that CFTI induces c-fos in the medial prefrontal cortex and nucleus accumbens, but not in the dorsolateral striatum, which is in line with the results using clozapine [58].…”

“…Of note, these mGlu1 receptor antagonists reduced maximal responses of L-glutamate [57,58], suggesting that both compounds acted as noncompetitive antagonists for the mGlu1 receptor. Thus, FITDC antagonized methamphetamine-induced locomotor hyperactivity and methamphetamine-disrupted PPI [59].…”

The Metabotropic Glutamate Receptor Subtype 5 Antagonist Fenobam Is Analgesic and Has Improved in Vivo Selectivity Compared with the Prototypical Antagonist 2-Methyl-6-(phenylethynyl)-pyridine

“…As reported here, these findings are similar to those seen when mice are pretreated with the prototypical mGlu5 antagonist MPEP (30 mg/kg). MPEP has been shown previously to reduce spontaneous nocifensive behaviors in the formalin test by several groups, with minimal effective doses in mice ranging from 10 mg/kg (Varty et al, 2005) to 30 mg/kg (Satow et al, 2008). We chose to make our comparison between fenobam and MPEP at a dose of 30 mg/kg because MPEP has been shown to be effective at 30 mg/kg in reducing formalin-induced nocifensive behaviors by multiple groups.…”