Antidepressant-like effects of mGluR1 and mGluR5 antagonists in the rat forced swim and the mouse tail suspension tests

Eur Neuropsychopharmacol. 2007 Feb;17(3):172-9. doi: 10.1016/j.euroneuro.2006.03.002. Epub 2006 Apr 21.

Abstract

Drugs that act to reduce glutamatergic neurotransmission such as NMDA receptor antagonists exert antidepressant-like effects in a variety of experimental paradigms, but their therapeutic application is limited by undesired side effects. In contrast, agents that reduce glutamatergic tone by blocking type I metabotropic glutamate receptors have been suggested to have more a favorable side-effect profile. The present study aimed to compare the effects of mGluR1 antagonist (EMQMCM; JNJ16567083, 3-ethyl-2-methyl-quinolin-6-yl)-(4-methoxy-cyclohexyl)-methanone methanesulfonate, 0.156-10 mg/kg) and mGluR5 antagonist (MTEP, [(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine, 1.25-10 mg/kg) in two behavioral screening assays commonly used to assess antidepressant-like activity. In the modified forced swim test in rats, imipramine (used as a positive control) decreased immobility (MED 40 mg/kg) and increased the duration of escape-oriented (climbing and diving; MED 20 mg/kg) behaviors. Both EMQMCM and MTEP decreased the floating duration (MED 1.25 and 2.5 mg/kg) and increased the duration of mobile behaviors (paddling and swimming; MED 2.5 and 5 mg/kg). EMQMCM but not MTEP increased the duration of escape behaviors (climbing and diving; MED 1.25 mg/kg). In the mouse tail suspension test, EMQMCM (5 but not 2.5, 10 and 25 mg/kg), 2-methyl-6-(phenylethynyl)-pyridine (MPEP, 10 but not 1 mg/kg) and MTEP (MED 25 mg/kg) decreased immobility scores. For EMQMCM, the dose-effect relationship was biphasic. With the exception of EMQMCM (10 mg/kg), locomotor activity in mice was not affected by treatments. The present study therefore suggests that acute blockade of mGluR5 and also of mGluR1 exerts antidepressant-like effects in behavioral despair tests in rats and mice.

MeSH terms

  • Animals
  • Antidepressive Agents / pharmacology*
  • Antidepressive Agents, Tricyclic / pharmacology
  • Depressive Disorder / psychology*
  • Dose-Response Relationship, Drug
  • Drug Evaluation, Preclinical
  • Hindlimb Suspension / psychology*
  • Imipramine / pharmacology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Motor Activity / drug effects
  • Pyridines / pharmacology
  • Rats
  • Rats, Wistar
  • Receptor, Metabotropic Glutamate 5
  • Receptors, Metabotropic Glutamate / antagonists & inhibitors*
  • Swimming / psychology*
  • Thiazoles / pharmacology

Substances

  • 3-((2-methyl-1,3-thiazol-4-yl)ethynyl)pyridine
  • Antidepressive Agents
  • Antidepressive Agents, Tricyclic
  • Grm5 protein, mouse
  • Grm5 protein, rat
  • Pyridines
  • Receptor, Metabotropic Glutamate 5
  • Receptors, Metabotropic Glutamate
  • Thiazoles
  • metabotropic glutamate receptor type 1
  • 6-methyl-2-(phenylethynyl)pyridine
  • Imipramine