THE EFFECT OF LORAZEPAM TOLERANCE AND WITHDRAWAL ON METABOTROPIC GLUTAMATE-RECEPTOR FUNCTION

Mice were exposed to lorazepam (4 mg/kg) or vehicle by continuous infu sion by implanted (s.c.) osmotic minipumps that were removed after 7 d ays. Dose-response curves for stimulation of phosphoinositide (PI) hyd rolysis by the selective metabotropic glutamate receptor (mGluR) agoni st, (1S,3R)-1-aminocyclopentane dicarboxylic acid [(IS,3R)-ACPD] were performed with cortical slices from mice treated with lorazepam or veh icle 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 w ith responses in control slices. The effect was blocked by the mGluR a ntagonist, L-2-amino-3-phosphonopropionate (L-AP3). Enhancement of PI hydrolysis in cortical slices from mice at 2 days of discontinuation f rom 7 days exposure to lorazepam was also observed with agonists of al pha, adrenergic and histamine receptors, but not with agonists of musc arinic or serotonin receptors when compared with responses in control slices. Intracerebroventricular infusion of L-AP3 significantly increa sed pentylenetetrazol-seizure threshold in mice withdrawn for 2 days f rom 7 days of exposure to lorazepam, but showed no effect in comparabl e vehicle-exposed mice. These data suggest that PI-coupled mGluRs may be implicated in regulation of GABAergic functionality as observed aft er withdrawal from prolonged exposure to lorazepam.