Abstract |
Mice were exposed to lorazepam (4 mg/kg) or vehicle by continuous infusion by implanted (s.c.) osmotic minipumps that were removed after 7 days. Dose-response curves for stimulation of phosphoinositide (PI) hydrolysis by the selective metabotropic glutamate receptor (mGluR) agonist, (1S,3R)-1-aminocyclopentane dicarboxylic acid [(1S,3R)-ACPD] were performed with cortical slices from mice treated with lorazepam or vehicle for 7 days and subject to 0, 1, 2, 3, 4 and 7 days of withdrawal. The efficacy of (1S,3R)-ACPD to stimulate PI hydrolysis was increased significantly at 2 and 3 days of lorazepam withdrawal when compared with responses in control slices. The effect was blocked by the mGluR antagonist, L-2-amino-3-phosphonopropionate (L-AP3). Enhancement of PI hydrolysis in cortical slices from mice at 2 days of discontinuation from 7 days exposure to lorazepam was also observed with agonists of alpha 1 adrenergic and histamine receptors, but not with agonists of muscarinic or serotonin receptors when compared with responses in control slices. Intracerebroventricular infusion of L-AP3 significantly increased pentylenetetrazol-seizure threshold in mice withdrawn for 2 days from 7 days of exposure to lorazepam, but showed no effect in comparable vehicle-exposed mice. These data suggest that PI-coupled mGluRs may be implicated in regulation of GABAergic functionality as observed after withdrawal from prolonged exposure to lorazepam.
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Authors | M Mortensen, P D Suzdak, C Thomsen |
Journal | The Journal of pharmacology and experimental therapeutics
(J Pharmacol Exp Ther)
Vol. 274
Issue 1
Pg. 155-63
(Jul 1995)
ISSN: 0022-3565 [Print] United States |
PMID | 7616393
(Publication Type: Journal Article)
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Chemical References |
- Phosphatidylinositols
- Receptors, GABA-A
- Receptors, Metabotropic Glutamate
- Cycloleucine
- 1-amino-1,3-dicarboxycyclopentane
- Cyclic AMP
- Protein Kinases
- Lorazepam
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Topics |
- Animals
- Cerebral Cortex
(drug effects, metabolism)
- Cyclic AMP
(biosynthesis)
- Cycloleucine
(analogs & derivatives, pharmacology)
- Drug Tolerance
- Hydrolysis
- In Vitro Techniques
- Lorazepam
(adverse effects, pharmacology)
- Male
- Mice
- Phosphatidylinositols
(metabolism)
- Protein Kinases
(drug effects)
- Receptors, GABA-A
(metabolism)
- Receptors, Metabotropic Glutamate
(antagonists & inhibitors, physiology)
- Seizures
(etiology)
- Substance Withdrawal Syndrome
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