Abstract
The interaction between 5-hydroxytryptamine2A (5-HT2A) 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.
Footnotes
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ABBREVIATIONS: mGlu, metabotropic glutamate; 5-HT, 5-hydroxytryptamine; PI, polyphosphoinositide; LY379268, (-)-2-oxa-4-aminocyclo[3.1.0]hexane-4,6-dicarboxylic acid; DOI, (±)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane; DHPG, 3,5-dihydroxyphenylglycine; LY341495, (2S, 1′S,2′S)-2-(9-xanthylmethyl)-2-(2′-carboxycyclopropyl)glycine; LY566332, N-(4′-cyano-biphenyl-3-yl)-N-(3-pyridinylmethyl)-ethanesulfonamide hydrochloride; MPEP, 2-methyl-6-(phenylethynyl)pyridine; BAY367620, (3aS,6aS)-6a-naphtalen-2-ylmethyl-5-methyliden-hexahydro-cyclopental[c]furan-1-on; MAPK, mitogen-activated protein kinase; ERK, extracellular signal-regulated kinase; PLC, phospholipase C; InsP, inositol monophosphate; PBS, phosphate-buffered saline; ANOVA, analysis of variance; PLSD, protected least significant difference; LY354740, (1S,2S,5R,6S)-2-aminobicyclo(3.1.0)hexane-2,6-dicarboxylic acid monohydrate.
- Accepted May 13, 2009.
- Received March 27, 2009.
- The American Society for Pharmacology and Experimental Therapeutics
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