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Vol. 55, No. 5, 1997
Issue release date: 1997
Section title: Original Papers
Pharmacology 1997;55:217–227
(DOI:10.1159/000139531)

The NMDA Receptor Competitive Antagonist CPP Modulates Benzodiazepine Tolerance and Discontinuation

Koff J.M. · Pritchard G.A. · Greenblatt D.J. · Miller L.G.
Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, Boston, Mass., USA

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Article / Publication Details

First-Page Preview
Abstract of Original Papers

Received: 4/7/1997
Accepted: 6/10/1997
Published online: 6/10/2008
Issue release date: 1997

Number of Print Pages: 11
Number of Figures: 0
Number of Tables: 0

ISSN: 0031-7012 (Print)
eISSN: 1423-0313 (Online)

For additional information: http://www.karger.com/PHA

Abstract

Benzodiazepine discontinuation is characterized by a syndrome of increased activity and reduced seizure threshold that is similar to effects mediated by the glutamatergic system. To elucidate the involvement of the glutamatergic system in benzodiazepine tolerance and discontinuation, we administered lorazepam, the NMDA antagonist CPP, and the combination of these compounds either concomitantly or consecutively to mice via osmotic pumps and evaluated pentylenetetrazole-induced seizure threshold, open-field activity, and benzodiazepine receptor binding during and after chronic administration. Animals receiving lorazepam alone developed partial tolerance at 7 days and complete tolerance at 14 days to the anticonvulsant effects of lorazepam. This effect was partly attenuated by CPP coadministration with lorazepam. This combination produced only partial tolerance. A reduction in seizure threshold was observed 4 days after discontinuation of lorazepam alone. This effect was abolished by coadministration of CPP with lorazepam and by CPP administration during the withdrawal period. Benzodiazepine binding in most structures examined was significantly reduced at 14 days during chronic lorazepam administration (versus 1 day), and coadministration of CPP did not alter this decrement. After lorazepam discontinuation, binding was increased at 4 and 7 days versus chronically treated animals and versus vehicle within the cerebral cortex. This effect was abolished by coadministration of CPP as well as by CPP administration during the lorazepam withdrawal period. These data support the involvement of the glutamatergic system in benzodiazepine tolerance and discontinuation.

© 1997 S. Karger AG, Basel


  

Author Contacts

Dr. David J. Greenblatt, Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, 136 Harrison Ave., Boston, MA 02111 (USA), Tel. +1 617 636 6997, fax +1 617 636 6738

  

Article Information

Received: April 7, 1997
Accepted: June 10, 1997
Published online: June 10, 2008
Number of Print Pages : 11

  

Publication Details

Pharmacology (International Journal of Experimental and Clinical Pharmacology)

Vol. 55, No. 5, Year 1997 (Cover Date: 1997)

Journal Editor: Donnerer J. (Graz), Billingsley M.L. (Hershey, Pa.), Maeyama K. (Matsuyama)
ISSN: 0031–7012 (Print), eISSN: 1423–0313 (Online)

For additional information: http://www.karger.com/PHA


Article / Publication Details

First-Page Preview
Abstract of Original Papers

Received: 4/7/1997
Accepted: 6/10/1997
Published online: 6/10/2008
Issue release date: 1997

Number of Print Pages: 11
Number of Figures: 0
Number of Tables: 0

ISSN: 0031-7012 (Print)
eISSN: 1423-0313 (Online)

For additional information: http://www.karger.com/PHA


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Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
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