10604933

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1

In prefrontal cortex, 5-hydroxytryptamine(2A) (5-HT(2A)) receptors have been linked to the action of hallucinogens and atypical antidepressant/antipsychotic drugs. Previously, we have shown in cortical layer V pyramidal cells that a nonselective metabotropic glutamate (mGlu) receptor agonist suppresses the induction of excitatory postsynaptic potentials/currents (EPSPs/EPSCs) via activation of 5-HT(2A) receptors. In this study, we tested the ability of the selective mGlu2/3 agonist (1S,2S,5R, 6S)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylate monohydrate (LY354740) and the selective mGlu2/3 antagonist 2S-2-amino-2-(1S, 2S-2-carboxycycloprop-1-yl)-3(xanthy-9-yl)propanoic acid (LY341495) to modulate serotonin(5-HT)-induced EPSPs and electrically evoked EPSPs by using intracellular recording from layer V pyramidal cells in medial prefrontal cortex. The mGlu2/3 antagonist LY341495 increased the frequency and amplitude of 5-HT-induced EPSCs, suggesting a role for mGlu2/3 receptors in mediating the action of endogenous glutamate on autoreceptors. Conversely, the mGlu2/3 agonist LY354740 was highly effective and potent (EC(50) = 89 nM) in suppressing glutamate release induced by 5-HT(2A) receptor activation in the medial prefrontal cortex, probably via a presynaptic mechanism. The mGlu2/3 antagonist LY341495 potently blocked the suppressant effect of LY354740 on 5-HT-induced EPSCs as well as electrically evoked early EPSPs. Autoradiography with the radioligands [(3)H]LY354740 and [(125)I](+/-)-1-(2, 5-dimethoxy-4-iodophenyl)-2-aminopropane showsa striking overlap of the laminar distribution of mGlu2/3 and 5-HT(2A) receptors in the medial prefrontal cortex that is not apparent in other cortical regions. These findings suggest a close coupling between mGlu2/3 and 5-HT(2A) receptors in the prefrontal cortex that may be relevant for novel therapeutic approaches in the treatment of neuropsychiatric syndromes such as depression and schizophrenia.

eng

IM

MEDLINE

0022-3565

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NLM

76-87

pubmed-meshheading:10604933-Amino Acids, pubmed-meshheading:10604933-Animals, pubmed-meshheading:10604933-Autoradiography, pubmed-meshheading:10604933-Bicyclo Compounds, pubmed-meshheading:10604933-Dose-Response Relationship, Drug, pubmed-meshheading:10604933-Drug Interactions, pubmed-meshheading:10604933-Electric Stimulation, pubmed-meshheading:10604933-Excitatory Amino Acid Agonists, pubmed-meshheading:10604933-Excitatory Amino Acid Antagonists, pubmed-meshheading:10604933-Excitatory Postsynaptic Potentials, pubmed-meshheading:10604933-Free Radical Scavengers, pubmed-meshheading:10604933-Glutamic Acid, pubmed-meshheading:10604933-Humans, pubmed-meshheading:10604933-Male, pubmed-meshheading:10604933-Membrane Potentials, pubmed-meshheading:10604933-Prefrontal Cortex, pubmed-meshheading:10604933-Protein Binding, pubmed-meshheading:10604933-Pyramidal Cells, pubmed-meshheading:10604933-Rats, pubmed-meshheading:10604933-Rats, Sprague-Dawley, pubmed-meshheading:10604933-Receptors, Metabotropic Glutamate, pubmed-meshheading:10604933-Receptors, Presynaptic, pubmed-meshheading:10604933-Serotonin, pubmed-meshheading:10604933-Xanthenes

Physiological antagonism between 5-hydroxytryptamine(2A) and group II metabotropic glutamate receptors in prefrontal cortex.

Journal Article, In Vitro, Research Support, U.S. Gov't, P.H.S., Research Support, Non-U.S. Gov't