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 Cartmell, J.
Right arrow Articles by Schoepp, D. D.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Cartmell, J.
Right arrow Articles by Schoepp, D. D.

Vol. 291, Issue 1, 161-170, October 1999

The Metabotropic Glutamate 2/3 Receptor Agonists LY354740 and LY379268 Selectively Attenuate Phencyclidine versus d-Amphetamine Motor Behaviors in Rats

Jayne Cartmell, James A. Monn and Darryle D. Schoepp

Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana

Previous animal studies have indicated that drugs targeted at metabotropic glutamate (mGlu) receptors may be useful for treatment of psychosis. In this article, the effects of the novel, potent, and selective mGlu2/3 receptor agonists LY354740 and LY379268, and the clinically effective agents clozapine and haloperidol, were investigated using phencyclidine (PCP; 5 mg/kg)- versus d-amphetamine (AMP; 3 mg/kg)-evoked motor activities. LY354740 (1-10 mg/kg s.c.), LY379268 (0.3-3 mg/kg s.c.), clozapine (1-10 mg/kg s.c.), and haloperidol (0.03-1 mg/kg s.c.) reversed the increases in ambulations, fine motor (nonambulatory) movements, and decreased time at rest evoked by PCP. Furthermore, the inhibitions of the PCP response by the mGlu2/3 agonist LY379268, but not by clozapine, were completely reversed by the selective mGlu2/3 receptor antagonist LY341495. Doses of LY354740 and LY379268 that blocked the effects on PCP had no effects on rotorod performance, and (with the exception of rearing behavior) had minimal effects on AMP-evoked motor activities. Clozapine blocked AMP-induced rearing but enhanced AMP-induced ambulations and fine movements at the lower doses (1 and 3 mg/kg). Unlike the mGlu2/3 agonists, the highest dose of clozapine tested (10 mg/kg) impaired animals on the rotorod. Haloperidol potently blocked all PCP and AMP effects, but only at doses associated with motor impairment. These data demonstrate that mGlu2/3 receptor agonists act via a unique mechanism to selectively block PCP-induced behaviors. Moreover, the marked mGlu2/3 receptor-mediated inhibitions of PCP-evoked behaviors by LY354740 and LY379268, with minimal effects on AMP, may indicate potential antipsychotic effects in humans in the absence of dopamine mediated extrapyramidal side effects.

0022-3565/99/2911-0161$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 1999 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
A. Satow, S. Maehara, S. Ise, H. Hikichi, M. Fukushima, G. Suzuki, T. Kimura, T. Tanak, S. Ito, H. Kawamoto, et al.
Pharmacological Effects of the Metabotropic Glutamate Receptor 1 Antagonist Compared with Those of the Metabotropic Glutamate Receptor 5 Antagonist and Metabotropic Glutamate Receptor 2/3 Agonist in Rodents: Detailed Investigations with a Selective Allosteric Metabotropic Glutamate Receptor 1 Antagonist, FTIDC [4-[1-(2-Fluoropyridine-3-yl)-5-methyl-1H-1,2,3-triazol-4-yl]-N-isopropyl-N-methyl-3,6-dihydropyridine-1(2H)-carboxamide]
J. Pharmacol. Exp. Ther., August 1, 2008; 326(2): 577 - 586.
[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
 J. Neurosci.Home page
M. E. Liechti, L. Lhuillier, K. Kaupmann, and A. Markou
Metabotropic Glutamate 2/3 Receptors in the Ventral Tegmental Area and the Nucleus Accumbens Shell Are Involved in Behaviors Relating to Nicotine Dependence
J. Neurosci., August 22, 2007; 27(34): 9077 - 9085.
[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
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]

Home page
 J. Neurosci.Home page
Y. Zhao, C. V. Dayas, H. Aujla, M. A. S. Baptista, R. Martin-Fardon, and F. Weiss
Activation of Group II Metabotropic Glutamate Receptors Attenuates Both Stress and Cue-Induced Ethanol-Seeking and Modulates c-fos Expression in the Hippocampus and Amygdala
J. Neurosci., September 27, 2006; 26(39): 9967 - 9974.
[Abstract] [Full Text] [PDF]

Home page
 J. Pharmacol. Exp. Ther.Home page
R. Galici, C. K. Jones, K. Hemstapat, Y. Nong, N. G. Echemendia, L. C. Williams, T. de Paulis, and P. J. Conn
Biphenyl-indanone A, a Positive Allosteric Modulator of the Metabotropic Glutamate Receptor Subtype 2, Has Antipsychotic- and Anxiolytic-Like Effects in Mice
J. Pharmacol. Exp. Ther., July 1, 2006; 318(1): 173 - 185.
[Abstract] [Full Text] [PDF]

Home page
 J. Pharmacol. Exp. Ther.Home page
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]

Home page
 J. Pharmacol. Exp. Ther.Home page
R. Galici, N. G. Echemendia, A. L. Rodriguez, and P. J. Conn
A Selective Allosteric Potentiator of Metabotropic Glutamate (mGlu) 2 Receptors Has Effects Similar to an Orthosteric mGlu2/3 Receptor Agonist in Mouse Models Predictive of Antipsychotic Activity
J. Pharmacol. Exp. Ther., December 1, 2005; 315(3): 1181 - 1187.
[Abstract] [Full Text] [PDF]

Home page
 Drug Metab. Dispos.Home page
J. K. James, M. Nakamura, A. Nakazato, K. E. Zhang, M. Cramer, J. Brunner, J. Cook, and W. G. Chen
METABOLISM AND DISPOSITION OF A POTENT GROUP II METABOTROPIC GLUTAMATE RECEPTOR AGONIST, IN RATS, DOGS, AND MONKEYS
Drug Metab. Dispos., September 1, 2005; 33(9): 1373 - 1381.
[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. Neurosci.Home page
M. A. S. Baptista, R. Martin-Fardon, and F. Weiss
Preferential Effects of the Metabotropic Glutamate 2/3 Receptor Agonist LY379268 on Conditioned Reinstatement versus Primary Reinforcement: Comparison between Cocaine and a Potent Conventional Reinforcer
J. Neurosci., May 19, 2004; 24(20): 4723 - 4727.
[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
 J. Neurosci.Home page
D. Robbe, G. Alonso, S. Chaumont, J. Bockaert, and O. J. Manzoni
Role of P/Q-Ca2+ Channels in Metabotropic Glutamate Receptor 2/3-Dependent Presynaptic Long-Term Depression at Nucleus Accumbens Synapses
J. Neurosci., June 1, 2002; 22(11): 4346 - 4356.
[Abstract] [Full Text] [PDF]

Home page
 Drug Metab. Dispos.Home page
J. T. Johnson, E. L. Mattiuz, S. H. Chay, J. L. Herman, W. J. Wheeler, K. Kassahun, S. P. Swanson, and D. L. Phillips
The Disposition, Metabolism, and Pharmacokinetics of a Selective Metabotropic Glutamate Receptor Agonist in Rats and Dogs
Drug Metab. Dispos., January 1, 2002; 30(1): 27 - 33.
[Abstract] [Full Text] [PDF]

Home page
 J. Neurophysiol.Home page
V. Neugebauer, P.-S. Chen, and W. D. Willis
Groups II and III Metabotropic Glutamate Receptors Differentially Modulate Brief and Prolonged Nociception in Primate STT Cells
J Neurophysiol, December 1, 2000; 84(6): 2998 - 3009.
[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 © 1999 by the American Society for Pharmacology and Experimental Therapeutics.