Activation of mGlu2/3 metabotropic glutamate receptors negatively regulates the stimulation of inositol phospholipid hydrolysis mediated by 5-hydroxytryptamine2A serotonin receptors in the frontal cortex of living mice

G. Molinaro, A. Traficante, B. Riozzi, L. Di Menna, M. Curto, S. Pallottino, F. Nicoletti, V. Bruno, Giuseppe Battaglia

Research output: Contribution to journalArticlepeer-review

36 Scopus citations

Abstract

The interaction between 5-hydroxytryptamine2A (5-HT 2A) serotonin receptors and metabotropic glutamate (mGlu) 2/3 receptors underlies the antipsychotic activity of mGlu2/3 receptor agonists in experimental animals and humans. The molecular nature of this interaction is only partially known. We here report for the first time that pharmacological activation of mGlu2/3 receptors attenuates the stimulation of polyphosphoinositide (PI) hydrolysis mediated by 5-HT2A receptors in the frontal cortex of living mice. Mice were injected intracerebroventricularly with [myo-3H]inositol and treated with drugs 1 h after a pretreatment with lithium, which blocks the conversion of inositol monophosphate into free inositol. Systemic injection of the mGlu2/3 receptor agonist ( - )-2-oxa-4-aminocyclo[3.1.0]hexane-4,6-dicarboxylic acid (LY379268) inhibited the stimulation of PI hydrolysis induced by the hallucinogenic 5-HT2A receptor agonist (±)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI)without affecting the stimulation by mGlu1/5 or muscarinic receptors. The action of LY379268 was prevented by the preferential mGlu2/3 receptor antagonist (2S,1′S,2′S)-2-(9-xanthylmethyl)-2-(2′-carboxycyclopropyl) glycine (LY341495). N-(4′-cyano-biphenyl-3-yl)-N-(3-pyridinylmethyl)- ethanesulfonamide hydrochloride (LY566332), a selective mGlu2 receptor enhancer, also reduced DOI-stimulated PI hydrolysis when combined with subthreshold doses of LY379268. Systemic LY379268 inhibited DOI-stimulated PI hydrolysis in mice lacking either mGlu2 or mGlu3 receptors but was inactive in double mGlu2/mGlu3 receptor knockout mice, suggesting that both mGlu2 and mGlu3 receptors interact with 5-HT2A receptors. Surprisingly, contrasting results were obtained in cortical slice preparations, where LY379268 amplified both DOI- and 3,5-dihydroxyphenylglycine-stimulated PI hydrolysis. Amplification was abrogated by the mGlu5 receptor antagonist 2-methyl-6-(phenylethynyl)pyridine, suggesting that experiments in brain slices are biased by an additional component of receptor-stimulated PI hydrolysis. This highlights the importance of in vivo models for the study of the interaction between 5-HT2A and mGlu2/3 receptors.

Original languageEnglish (US)
Pages (from-to)379-387
Number of pages9
JournalMolecular Pharmacology
Volume76
Issue number2
DOIs
StatePublished - Aug 1 2009

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

Fingerprint Dive into the research topics of 'Activation of mGlu2/3 metabotropic glutamate receptors negatively regulates the stimulation of inositol phospholipid hydrolysis mediated by 5-hydroxytryptamine<sub>2A</sub> serotonin receptors in the frontal cortex of living mice'. Together they form a unique fingerprint.

Cite this