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.
The interaction between 5-hydroxytryptamine(2A) (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-HT(2A) receptors in the frontal cortex of living mice. Mice were injected intracerebroventricularly with [myo-(3)H]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-HT(2A) 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-HT(2A) 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-HT(2A) and mGlu2/3 receptors.
Instituto Neurologico Mediterraneo Neuromed, Pozzilli, Italy.
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Molinaro
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Traficante
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Riozzi
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Di Menna
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Curto
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Pallottino
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Nicoletti
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Bruno
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Battaglia
D000596:Amino Acids / Q000494:pharmacology; D000662:Amphetamines / Q000494:pharmacology; D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005625:Frontal Lobe / Q000187:drug effects*; D006868:Hydrolysis; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D010716:Phosphatidylinositols / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology; D044402:Receptor, Serotonin, 5-HT2A / Q000378:metabolism*; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000502:physiology; D013449:Sulfonamides / Q000494:pharmacology; D014966:Xanthenes / Q000494:pharmacology
D000596:Amino Acids; D000662:Amphetamines; D019086:Bridged Bicyclo Compounds, Heterocyclic; D018691:Excitatory Amino Acid Antagonists; C114624:LY 341495; C118218:LY 379268; C542802:N-(4'-cyanobiphenyl-3-yl)-N-(3-pyridinylmethyl)ethanesulfonamide; D010716:Phosphatidylinositols; D011725:Pyridines; D044402:Receptor, Serotonin, 5-HT2A; D018094:Receptors, Metabotropic Glutamate; D013449:Sulfonamides; D014966:Xanthenes; C108822:metabotropic glutamate receptor 2; C102718:metabotropic glutamate receptor 3; C015952:4-iodo-2,5-dimethoxyphenylisopropylamine