Effects of valproate and lorazepam on experimental anxiety: tolerance, withdrawal, and role of clonidine.

The anxiolytic-like effects tolerance and withdrawal from chronic treatment with sodium valproate [200, 300, and 400 mg/kg, intraperitoneally (i.p.)] were compared with those of a known anxiolytic drug, lorazepam (0.025, 0.05, and 0.10 mg/kg, i.p.), in the light-dark aversion test in mice. Furthermore, we investigated whether acute treatment with clonidine, 0.03 mg/kg i.p., an alpha 2-adrenoceptor agonist, could reduce the increased anxiety on withdrawal from chronic treatment. Mice were given 14 daily i.p. injections of valproate, lorazepam, or vehicle and were tested in the light-dark aversion test 30 min or 24 or 48 h after the last drug or vehicle administration. Results showed that both acute and chronic valproate treatment reduced the aversion of mice for the light area, as well as increased the number of transitions, thus indicating an anxiolytic-like potential. Furthermore, in contrast to lorazepam, tolerance to the anxiolytic-like effects of valproate did not occur, and withdrawal from chronic treatment (300 mg/kg, i.p.) in our behavioral paradigm was not associated with any behavioral disturbances referring to an increased anxiety state. Finally, low doses of clonidine (0.03 mg/kg, i.p.) were shown to have anxiolytic properties and to reverse the anxiogenic effects of lorazepam on withdrawal.