title: The effect of lorazepam tolerance and withdrawal on metabotropic glutamate receptor function.
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 Intracerebroventricular infusion of L-AP3 significantly increased pentylenetetrazol-seizure threshold in mice withdrawn for 2 days from 7 days of exposure to lorazepam, but showed no effect in comparable vehicle-exposed mice.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.
authors.affiliation: Department of Receptor Neurochemistry, Novo Nordisk A/S, Måløv, Denmark.
authors.forename: M
authors.initials: M
authors.lastname: Mortensen
authors.forename: P D
authors.initials: PD
authors.lastname: Suzdak
authors.forename: C
authors.initials: C
authors.lastname: Thomsen
mesh_terms: D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D000242:Cyclic AMP / Q000096:biosynthesis; D003515:Cycloleucine / Q000031:analogs & derivatives / Q000494:pharmacology; D004361:Drug Tolerance; D006868:Hydrolysis; D066298:In Vitro Techniques; D008140:Lorazepam / Q000009:adverse effects / Q000494:pharmacology*; D008297:Male; D051379:Mice; D010716:Phosphatidylinositols / Q000378:metabolism; D011494:Protein Kinases / Q000187:drug effects; D011963:Receptors, GABA-A / Q000378:metabolism; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors / Q000502:physiology*; D012640:Seizures / Q000209:etiology; D013375:Substance Withdrawal Syndrome
chemical_list: D010716:Phosphatidylinositols; D011963:Receptors, GABA-A; D018094:Receptors, Metabotropic Glutamate; D003515:Cycloleucine; C036361:1-amino-1,3-dicarboxycyclopentane; D000242:Cyclic AMP; D011494:Protein Kinases; D008140:Lorazepam