19439499

pubmed:Citation

2

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.

http://linkedlifedata.com/resource/pubmed/journal/0035623

http://linkedlifedata.com/resource/pubmed/chemical/4-iodo-2,5-dimethoxyphenylisopropyla..., http://linkedlifedata.com/resource/pubmed/chemical/Amino Acids, http://linkedlifedata.com/resource/pubmed/chemical/Amphetamines, http://linkedlifedata.com/resource/pubmed/chemical/Bicyclo Compounds, Heterocyclic, http://linkedlifedata.com/resource/pubmed/chemical/Excitatory Amino Acid Antagonists, http://linkedlifedata.com/resource/pubmed/chemical/LY 341495, http://linkedlifedata.com/resource/pubmed/chemical/LY 379268, http://linkedlifedata.com/resource/pubmed/chemical/Phosphatidylinositols, http://linkedlifedata.com/resource/pubmed/chemical/Pyridines, http://linkedlifedata.com/resource/pubmed/chemical/Receptor, Serotonin, 5-HT2A, http://linkedlifedata.com/resource/pubmed/chemical/Receptors, Metabotropic Glutamate, http://linkedlifedata.com/resource/pubmed/chemical/Sulfonamides, http://linkedlifedata.com/resource/pubmed/chemical/Xanthenes, http://linkedlifedata.com/resource/pubmed/chemical/metabotropic glutamate receptor 2, http://linkedlifedata.com/resource/pubmed/chemical/metabotropic glutamate receptor 3

Aug

pubmed-author:BattagliaGG, pubmed-author:BrunoVV, pubmed-author:CurtoMM, pubmed-author:Di MennaLL, pubmed-author:MolinariAA, pubmed-author:NicolettiFF, pubmed-author:PallottinoSS, pubmed-author:RiozziBB, pubmed-author:TraficanteAA

76

Y

pubmed-meshheading:19439499-Amino Acids, pubmed-meshheading:19439499-Amphetamines, pubmed-meshheading:19439499-Animals, pubmed-meshheading:19439499-Bicyclo Compounds, Heterocyclic, pubmed-meshheading:19439499-Dose-Response Relationship, Drug, pubmed-meshheading:19439499-Excitatory Amino Acid Antagonists, pubmed-meshheading:19439499-Frontal Lobe, pubmed-meshheading:19439499-Hydrolysis, pubmed-meshheading:19439499-Male, pubmed-meshheading:19439499-Mice, pubmed-meshheading:19439499-Mice, Inbred Strains, pubmed-meshheading:19439499-Mice, Knockout, pubmed-meshheading:19439499-Phosphatidylinositols, pubmed-meshheading:19439499-Pyridines, pubmed-meshheading:19439499-Receptor, Serotonin, 5-HT2A, pubmed-meshheading:19439499-Receptors, Metabotropic Glutamate, pubmed-meshheading:19439499-Sulfonamides, pubmed-meshheading:19439499-Xanthenes

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.

Journal Article