HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: 93/4/1989    most recent 00875.2004v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (1) Citing Articles via Google Scholar Google Scholar Articles by Homayoun, H. Articles by Moghaddam, B. Search for Related Content PubMed PubMed Citation Articles by Homayoun, H. Articles by Moghaddam, B.

Activation of Metabotropic Glutamate 2/3 Receptors Reverses the Effects of NMDA Receptor Hypofunction on Prefrontal Cortex Unit Activity in Awake Rats

Department of Neuroscience, University of Pittsburgh, Pittsburgh, Pennsylvania

Submitted 24 August 2004; accepted in final form 4 December 2004

Systemic exposure to N-methyl-D-aspartate (NMDA) receptor antagonists can lead to psychosis and prefrontal cortex (PFC)–dependent behavioral impairments. Agonists of metabotropic glutamate 2/3 (mGlu2/3) receptors ameliorate the adverse behavioral effects of NMDA antagonists in humans and laboratory animals, and are being considered as a novel treatment for some symptoms of schizophrenia. Despite the compelling behavioral data, the cellular mechanisms by which potentiation of mGlu2/3 receptor function attenuates the effects of NMDA receptor hypofunction remain unclear. In freely moving rats, we recorded the response of medial PFC (prelimbic) single units to treatment with the NMDA antagonist MK801 and assessed the dose-dependent effects of pre- or posttreatment with the mGlu2/3 receptor agonist LY354740 on this response. NMDA receptor antagonist-induced behavioral stereotypy was measured during recording because it may relate to the psychotomimetic properties of this treatment and is dependent on the functional integrity of the PFC. In most PFC neurons, systemic administration of MK801 increased the spontaneous firing rate, decreased the variability of spike trains, and disrupted patterns of spontaneous bursts. Given alone, LY354740 (1, 3, and 10 mg/kg) decreased spontaneous activity of PFC neurons at the highest dose. Pre- or posttreatment with LY354740 blocked MK801-induced changes on firing rate, burst activity, and variability of spike activity. These physiological changes coincided with a reduction in MK801-induced behavioral stereotypy by LY354740. These data indicate that activation of mGlu2/3 receptors reduces the disruptive effects of NMDA receptor hypofunction on the spontaneous spike activity and bursting of PFC neurons. This mechanism may provide a physiological basis for reversal of NMDA antagonist-induced behaviors by mGlu2/3 agonists.

This article has been cited by other articles:

				S. Ghose, K. A. Gleason, B. W. Potts, K. Lewis-Amezcua, and C. A. Tamminga Differential Expression of Metabotropic Glutamate Receptors 2 and 3 in Schizophrenia: A Mechanism for Antipsychotic Drug Action? Am J Psychiatry, July 1, 2009; 166(7): 812 - 820. [Abstract] [Full Text] [PDF]

				M. V. S. Varma, A. H. Eriksson, G. Sawada, Y. A. Pak, E. J. Perkins, and C. L. Zimmerman Transepithelial Transport of the Group II Metabotropic Glutamate 2/3 Receptor Agonist (1S,2S,5R,6S)-2-Aminobicyclo[3.1.0]hexane-2,6-dicarboxylate (LY354740) and Its Prodrug (1S,2S,5R,6S)-2-[(2'S)-(2'-Amino)propionyl]aminobicyclo[3.1.0]hexane-2,6-dicarboxylate (LY544344) Drug Metab. Dispos., January 1, 2009; 37(1): 211 - 220. [Abstract] [Full Text] [PDF]

				B. R. Miller, A. G. Walker, A. S. Shah, S. J. Barton, and G. V. Rebec Dysregulated Information Processing by Medium Spiny Neurons in Striatum of Freely Behaving Mouse Models of Huntington's Disease J Neurophysiol, October 1, 2008; 100(4): 2205 - 2216. [Abstract] [Full Text] [PDF]

				A. G. Walker, B. R. Miller, J. N. Fritsch, S. J. Barton, and G. V. Rebec Altered Information Processing in the Prefrontal Cortex of Huntington's Disease Mouse Models J. Neurosci., September 3, 2008; 28(36): 8973 - 8982. [Abstract] [Full Text] [PDF]

				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]

				C. H. Large Do NMDA receptor antagonist models of schizophrenia predict the clinical efficacy of antipsychotic drugs? J Psychopharmacol, May 1, 2007; 21(3): 283 - 301. [Abstract] [PDF]

				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]

				A. Bespalov, A.-L. Jongen-Relo, M. van Gaalen, S. Harich, H. Schoemaker, and G. Gross Habituation Deficits Induced by Metabotropic Glutamate Receptors 2/3 Receptor Blockade in Mice: Reversal by Antipsychotic Drugs J. Pharmacol. Exp. Ther., February 1, 2007; 320(2): 944 - 950. [Abstract] [Full Text] [PDF]

				L. M. Rorick-Kehn, E. J. Perkins, K. M. Knitowski, J. C. Hart, B. G. Johnson, D. D. Schoepp, and D. L. McKinzie Improved Bioavailability of the mGlu2/3 Receptor Agonist LY354740 Using a Prodrug Strategy: In Vivo Pharmacology of LY544344 J. Pharmacol. Exp. Ther., February 1, 2006; 316(2): 905 - 913. [Abstract] [Full Text] [PDF]