JPET

Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Marek, G. J.
Right arrow Articles by Aghajanian, G. K.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Marek, G. J.
Right arrow Articles by Aghajanian, G. K.
Right arrowPubmed/NCBI databases
*Compound via MeSH
*Substance via MeSH
Hazardous Substances DB
*GLUTAMIC ACID HYDROCHLORIDE

Vol. 292, Issue 1, 76-87, January 2000

Physiological Antagonism between 5-Hydroxytryptamine2A and Group II Metabotropic Glutamate Receptors in Prefrontal Cortex1

Gerard J. Marek, Rebecca A. Wright, Darryle D. Schoepp, James A. Monn and George K. Aghajanian

Departments of Psychiatry and Pharmacology, Yale University School of Medicine, Ribicoff Research Facilities of the Connecticut Mental Health Center, New Haven, Connecticut (G.J.M., G.K.A.); Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana (R.A.W., D.D.S., J.A.M.).

In prefrontal cortex, 5-hydroxytryptamine2A (5-HT2A) 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-HT2A 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 (EC50 = 89 nM) in suppressing glutamate release induced by 5-HT2A 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 [3H]LY354740 and [125I](±)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane showsa striking overlap of the laminar distribution of mGlu2/3 and 5-HT2A 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-HT2A 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 This work was supported by United States Public Health Service Grants K08 Award (National Institute of Mental Health; G.J.M.) and MH17871 (National Institute of Mental Health; G.K.A.), a National Alliance for Research on Schizophrenia and Depression (NARSAD) 1999 Fairfax Investigator Award (G.J.M.), the State of Connecticut (G.J.M., G.K.A.), and Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN.

0022-3565/0/2921-0076$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2000 by The American Society for Pharmacology and Experimental Therapeutics


This article has been cited by other articles:


Home page
 J. Pharmacol. Exp. Ther.Home page
P. A. Ardayfio, M. J. Benvenga, S. F. Chaney, P. L. Love, J. Catlow, S. P. Swanson, and G. J. Marek
The 5-Hydroxytryptamine2A Receptor Antagonist R-(+)-{alpha}-(2,3-Dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl-4-piperidinemethanol (M100907) Attenuates Impulsivity after Both Drug-Induced Disruption (Dizocilpine) and Enhancement (Antidepressant Drugs) of Differential-Reinforcement-of-Low-Rate 72-s Behavior in the Rat
J. Pharmacol. Exp. Ther., December 1, 2008; 327(3): 891 - 897.
[Abstract] [Full Text] [PDF]

Home page
 J. Pharmacol. Exp. Ther.Home page
M. J. Fell, K. A. Svensson, B. G. Johnson, and D. D. Schoepp
Evidence for the Role of Metabotropic Glutamate (mGlu)2 Not mGlu3 Receptors in the Preclinical Antipsychotic Pharmacology of the mGlu2/3 Receptor Agonist (-)-(1R,4S,5S,6S)-4-Amino-2-sulfonylbicyclo[3.1.0]hexane-4,6-dicarboxylic Acid (LY404039)
J. Pharmacol. Exp. Ther., July 1, 2008; 326(1): 209 - 217.
[Abstract] [Full Text] [PDF]

Home page
 J PsychopharmacolHome page
P. Harrison, L. Lyon, L. Sartorius, P. Burnet, and T. Lane
Review: The group II metabotropic glutamate receptor 3 (mGluR3, mGlu3, GRM3): expression, function and involvement in schizophrenia
J Psychopharmacol, May 1, 2008; 22(3): 308 - 322.
[Abstract] [PDF]

Home page
 Mol. Interv.Home page
P. J. Conn, C. Tamminga, D. D. Schoepp, and C. Lindsley
Schizophrenia: Moving Beyond Monoamine Antagonists
Mol. Interv., April 1, 2008; 8(2): 99 - 107.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Pharmacol.Home page
M. A. Benneyworth, Z. Xiang, R. L. Smith, E. E. Garcia, P. J. Conn, and E. Sanders-Bush
A Selective Positive Allosteric Modulator of Metabotropic Glutamate Receptor Subtype 2 Blocks a Hallucinogenic Drug Model of Psychosis
Mol. Pharmacol., August 1, 2007; 72(2): 477 - 484.
[Abstract] [Full Text] [PDF]

Home page
 J. Pharmacol. Exp. Ther.Home page
L. M. Rorick-Kehn, B. G. Johnson, J. L. Burkey, R. A. Wright, D. O. Calligaro, G. J. Marek, E. S. Nisenbaum, J. T. Catlow, A. E. Kingston, D. D. Giera, et al.
Pharmacological and Pharmacokinetic Properties of a Structurally Novel, Potent, and Selective Metabotropic Glutamate 2/3 Receptor Agonist: In Vitro Characterization of Agonist (-)-(1R,4S,5S,6S)-4-Amino-2-sulfonylbicyclo[3.1.0]-hexane-4,6-dicarboxylic Acid (LY404039)
J. Pharmacol. Exp. Ther., April 1, 2007; 321(1): 308 - 317.
[Abstract] [Full Text] [PDF]

Home page
 J. Pharmacol. Exp. Ther.Home page
C. Zhang and G. J. Marek
Group III Metabotropic Glutamate Receptor Agonists Selectively Suppress Excitatory Synaptic Currents in the Rat Prefrontal Cortex Induced by 5-Hydroxytryptamine2A Receptor Activation
J. Pharmacol. Exp. Ther., January 1, 2007; 320(1): 437 - 447.
[Abstract] [Full Text] [PDF]

Home page
 J. Neurophysiol.Home page
J. P. Tyszkiewicz and Z. Yan
{beta}-Amyloid Peptides Impair PKC-Dependent Functions of Metabotropic Glutamate Receptors in Prefrontal Cortical Neurons
J Neurophysiol, June 1, 2005; 93(6): 3102 - 3111.
[Abstract] [Full Text] [PDF]

Home page
 J. Neurophysiol.Home page
H. Homayoun, M. E. Jackson, and B. Moghaddam
Activation of Metabotropic Glutamate 2/3 Receptors Reverses the Effects of NMDA Receptor Hypofunction on Prefrontal Cortex Unit Activity in Awake Rats
J Neurophysiol, April 1, 2005; 93(4): 1989 - 2001.
[Abstract] [Full Text] [PDF]

Home page
 J. Physiol.Home page
J. P. Tyszkiewicz, Z. Gu, X. Wang, X. Cai, and Z. Yan
Group II metabotropic glutamate receptors enhance NMDA receptor currents via a protein kinase C-dependent mechanism in pyramidal neurones of rat prefrontal cortex
J. Physiol., February 1, 2004; 554(3): 765 - 777.
[Abstract] [Full Text] [PDF]

Home page
 Physiol. GenomicsHome page
S. Kaiser and L. K. Nisenbaum
Evaluation of common gene expression patterns in the rat nervous system
Physiol Genomics, December 16, 2003; 16(1): 1 - 7.
[Abstract] [Full Text] [PDF]

Home page
 J. Pharmacol. Exp. Ther.Home page
C. J. Swanson and D. D. Schoepp
The Group II Metabotropic Glutamate Receptor Agonist (-)-2-Oxa-4-aminobicyclo[3.1.0.]hexane-4,6-dicarboxylate (LY379268) and Clozapine Reverse Phencyclidine-Induced Behaviors in Monoamine-Depleted Rats
J. Pharmacol. Exp. Ther., December 1, 2002; 303(3): 919 - 927.
[Abstract] [Full Text] [PDF]

Home page
 Adv. Psychiatr. Treat.Home page
E. M. Tsapakis and M. J. Travis
Glutamate and psychiatric disorders
Advan. Psychiatr. Treat., May 1, 2002; 8(3): 189 - 197.
[Full Text] [PDF]

Home page
 J. Neurosci.Home page
R. Martin-Ruiz, M. V. Puig, P. Celada, D. A. Shapiro, B. L. Roth, G. Mengod, and F. Artigas
Control of Serotonergic Function in Medial Prefrontal Cortex by Serotonin-2A Receptors through a Glutamate-Dependent Mechanism
J. Neurosci., December 15, 2001; 21(24): 9856 - 9866.
[Abstract] [Full Text] [PDF]

Home page
 J. Pharmacol. Exp. Ther.Home page
D. D. Schoepp
Unveiling the Functions of Presynaptic Metabotropic Glutamate Receptors in the Central Nervous System
J. Pharmacol. Exp. Ther., October 1, 2001; 299(1): 12 - 20.
[Abstract] [Full Text] [PDF]

Home page
 J. Pharmacol. Exp. Ther.Home page
G. G. Blakley, L. A. Pohorecky, and D. Benjamin
Bidirectional Changes in Ethanol Consumption in Rats with Site-Specific Antisense Down-Regulation of 5-Hydroxytryptamine2A Receptors in Brain
J. Pharmacol. Exp. Ther., October 1, 2001; 299(1): 277 - 289.
[Abstract] [Full Text] [PDF]

Home page
 J. Neurosci.Home page
J. L. Scruggs, S. Patel, M. Bubser, and A. Y. Deutch
DOI-Induced Activation of the Cortex: Dependence on 5-HT2A Heteroceptors on Thalamocortical Glutamatergic Neurons
J. Neurosci., December 1, 2000; 20(23): 8846 - 8852.
[Abstract] [Full Text] [PDF]


Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
All ASPET Journals Molecular Pharmacology Pharmacological Reviews
Molecular Interventions Drug Metabolism and Disposition

Copyright © 2000 by the American Society for Pharmacology and Experimental Therapeutics.