The effect of lorazepam tolerance and withdrawal on metabotropic glutamate receptor function.

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 Intracerebroventricular infusion of L-AP3 significantly increased pentylenetetrazol-seizure threshold in mice withdrawn for 2 days from 7 days of exposure to lorazepam, but showed no effect in comparable vehicle-exposed mice.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.