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

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.

[1]  G. Aghajanian,et al.  Serotonin–Glutamate Interactions: A New Target for Antipsychotic Drugs , 1999, Neuropsychopharmacology.

[2]  D. Jane,et al.  Pharmacological agents acting at subtypes of metabotropic glutamate receptors , 1999, Neuropharmacology.

[3]  P. Ornstein,et al.  [3H]-LY341495 as a novel antagonist radioligand for group II metabotropic glutamate (mGlu) receptors: characterization of binding to membranes of mGlu receptor subtype expressing cells , 1999, Neuropharmacology.

[4]  G. Aghajanian,et al.  Serotonin, via 5-HT2A receptors, increases EPSCs in layer V pyramidal cells of prefrontal cortex by an asynchronous mode of glutamate release , 1999, Brain Research.

[5]  J. Grutsch,et al.  Synthesis, pharmacological characterization, and molecular modeling of heterobicyclic amino acids related to (+)-2-aminobicyclo[3.1.0] hexane-2,6-dicarboxylic acid (LY354740): identification of two new potent, selective, and systemically active agonists for group II metabotropic glutamate receptors. , 1999, Journal of medicinal chemistry.

[6]  G. Aghajanian,et al.  5-HT2A receptor or alpha1-adrenoceptor activation induces excitatory postsynaptic currents in layer V pyramidal cells of the medial prefrontal cortex. , 1999, European journal of pharmacology.

[7]  G. Aghajanian,et al.  The electrophysiology of prefrontal serotonin systems: therapeutic implications for mood and psychosis , 1998, Biological Psychiatry.

[8]  Z. Bortolotto,et al.  The potent mGlu receptor antagonist LY341495 identifies roles for both cloned and novel mGlu receptors in hippocampal synaptic plasticity , 1998, Neuropharmacology.

[9]  W. Kroeze,et al.  The molecular biology of serotonin receptors: therapeutic implications for the interface of mood and psychosis , 1998, Biological Psychiatry.

[10]  Andreas Bäbler,et al.  Psilocybin induces schizophrenia‐like psychosis in humans via a serotonin‐2 agonist action , 1998, Neuroreport.

[11]  B. Moghaddam,et al.  Reversal of phencyclidine effects by a group II metabotropic glutamate receptor agonist in rats. , 1998, Science.

[12]  D. Schoepp,et al.  Potent, stereoselective, and brain region selective modulation of second messengers in the rat brain by (+)LY354740, a novel group II metabotropic glutamate receptor agonist , 1998, Naunyn-Schmiedeberg's Archives of Pharmacology.

[13]  G. Aghajanian,et al.  5-Hydroxytryptamine-induced excitatory postsynaptic currents in neocortical layer V pyramidal cells: suppression by μ-opiate receptor activation , 1998, Neuroscience.

[14]  R. Post,et al.  Bidirectional Synaptic Plasticity in the Rat Basolateral Amygdala: Characterization of an Activity-Dependent Switch Sensitive to the Presynaptic Metabotropic Glutamate Receptor Antagonist 2S-α-Ethylglutamic Acid , 1998, The Journal of Neuroscience.

[15]  D. Schoepp,et al.  Anxiolytic and side-effect profile of LY354740: a potent, highly selective, orally active agonist for group II metabotropic glutamate receptors. , 1998, The Journal of pharmacology and experimental therapeutics.

[16]  P. Ornstein,et al.  LY341495 is a nanomolar potent and selective antagonist of group II metabotropic glutamate receptors , 1998, Neuropharmacology.

[17]  N. Mizuno,et al.  Distribution of a metabotropic glutamate receptor, mGluR2, in the central nervous system of the rat and mouse: an immunohistochemical study with a monoclonal antibody , 1998, Neurosciences research.

[18]  B. Sakmann,et al.  Calcium action potentials restricted to distal apical dendrites of rat neocortical pyramidal neurons , 1997, The Journal of physiology.

[19]  D. Schoepp,et al.  LY354740: a metabotropic glutamate receptor agonist which ameliorates symptoms of nicotine withdrawal in rats , 1997, Neuropharmacology.

[20]  D. Schoepp,et al.  Design, Synthesis, and Pharmacological Characterization of (+)-2- Aminobicyclo(3.1.0)hexane-2,6-dicarboxylic Acid (LY354740): A Potent, Selective, and Orally Active Group 2 Metabotropic Glutamate Receptor Agonist Possessing Anticonvulsant and Anxiolytic Properties. , 1997 .

[21]  P. Schwindt,et al.  Local and propagated dendritic action potentials evoked by glutamate iontophoresis on rat neocortical pyramidal neurons. , 1997, Journal of neurophysiology.

[22]  G. Aghajanian,et al.  Serotonin Induces Excitatory Postsynaptic Potentials in Apical Dendrites of Neocortical Pyramidal Cells , 1997, Neuropharmacology.

[23]  D. Schoepp,et al.  Design, synthesis, and pharmacological characterization of (+)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (LY354740): a potent, selective, and orally active group 2 metabotropic glutamate receptor agonist possessing anticonvulsant and anxiolytic properties. , 1997, Journal of medicinal chemistry.

[24]  Paul Antoine Salin,et al.  Use-dependent increases in glutamate concentration activate presynaptic metabotropic glutamate receptors , 1997, Nature.

[25]  H. Schild,et al.  SOME QUANTITATIVE USES OF DRUG ANTAGONISTS , 1997, British journal of pharmacology and chemotherapy.

[26]  D. Schoepp,et al.  LY354740 is a Potent and Highly Selective Group II Metabotropic Glutamate Receptor Agonist in Cells Expressing Human Glutamate Receptors , 1997, Neuropharmacology.

[27]  R. Petralia,et al.  The metabotropic glutamate receptors, MGLUR2 and MGLUR3, show unique postsynaptic, presynaptic and glial localizations , 1996, Neuroscience.

[28]  S. Nakanishi,et al.  Distributions of the mRNAs for L‐2‐amino‐4‐phosphonobutyrate‐sensitive metabotropic glutamate receptors, mGluR4 and mGluR7, in the rat brain , 1995, The Journal of comparative neurology.

[29]  D. Lovinger,et al.  Metabotropic glutamate receptor-mediated presynaptic depression at corticostriatal synapses involves mGLuR2 or 3. , 1995, Journal of neurophysiology.

[30]  Y. Goda,et al.  Two components of transmitter release at a central synapse. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[31]  D. Schoepp,et al.  Distribution and Ontogeny of 1S,3R‐1‐Aminocyclopentane‐1,3‐Dicarboxylic Acid‐Sensitive and Quisqualate‐Insensitive [3H]Glutamate Binding Sites in the Rat Brain , 1994, Journal of neurochemistry.

[32]  S. Nakanishi,et al.  Distribution of the mRNA for a metabotropic glutamate receptor (mGluR3) in the rat brain: An in situ hybridization study , 1993, The Journal of comparative neurology.

[33]  S. Nakanishi,et al.  Distribution of the messenger RNA for a metabotropic glutamate receptor, mGluR2, in the central nervous system of the rat , 1993, Neuroscience.

[34]  W. Kloot.  The regulation of quantal size , 1991, Progress in Neurobiology.

[35]  H. Groenewegen,et al.  Restricted cortical termination fields of the midline and intralaminar thalamic nuclei in the rat , 1991, Neuroscience.

[36]  B. Connors,et al.  Intrinsic firing patterns of diverse neocortical neurons , 1990, Trends in Neurosciences.

[37]  M. Molliver,et al.  Correspondence between 5-HT2 receptors and serotonergic axons in rat neocortex , 1988, Brain Research.

[38]  E. Richelson,et al.  Antagonism by antidepressants of serotonin S1 and S2 receptors of normal human brain in vitro. , 1986, European journal of pharmacology.

[39]  D. McCormick,et al.  Comparative electrophysiology of pyramidal and sparsely spiny stellate neurons of the neocortex. , 1985, Journal of neurophysiology.

[40]  E. Richelson,et al.  Antagonism by antidepressants of neurotransmitter receptors of normal human brain in vitro. , 1984, The Journal of pharmacology and experimental therapeutics.

[41]  J. Pin,et al.  Pharmacology and functions of metabotropic glutamate receptors. , 1997, Annual review of pharmacology and toxicology.

[42]  G. Westbrook,et al.  Cloning and expression of rat metabotropic glutamate receptor 8 reveals a distinct pharmacological profile. , 1997, Molecular pharmacology.

[43]  T. Boer.  The pharmacologic profile of mirtazapine. , 1996 .

[44]  A. S. Eison,et al.  Nefazodone: preclinical pharmacology of a new antidepressant. , 1990, Psychopharmacology bulletin.

[45]  G. Aghajanian,et al.  Intracellular studies in the facial nucleus illustrating a simple new method for obtaining viable motoneurons in adult rat brain slices , 1989, Synapse.

[46]  G. Paxinos,et al.  The Rat Brain in Stereotaxic Coordinates , 1983 .