THE NITRIC-OXIDE SYNTHASE INHIBITOR 7-NITROINDAZOLE DISPLAYS ENHANCEDANXIOLYTIC EFFICACY WITHOUT TOLERANCE IN RATS FOLLOWING SUBCHRONIC ADMINISTRATION

The nitric oxide synthase inhibitor 7-nitroindazole (7-NI) dose-depend ently (3.0-30.0 mg/kg) displayed anxiolytic activity, as measured by a n increase in open arm exploration time in the elevated plus-maze (EPM ), following intraperitoneal (i.p.) administration in rats. Acute admi nistration of 7-NI at 30.0 mg/kg significantly (P < 0.05) increased op en arm exploration time by 176% compared to vehicle control, similar t o the benzodiazepine diazepam at 1.0 and 3.0 mg/kg (+ 191 and + 200%, respectively). However, 39 h following subchronic 5-day administration of diazepam twice daily (bid) at 3.0 mg/kg, diazepam was devoid of an xiolytic activity at 1.0 mg/kg, as measured by no difference in open a rm exploration time compared to vehicle control, while the 3.0 mg/kg d ose still produced a significant (P < 0.05) 175% increase in open arm exploration time. In contrast, following subchronic administration of 7-NI (30.0 mg/kg, bid), a significant (P < 0.01) enhancement in open a rm exploration time was observed at 30.0 mg/kg (+ 665% compared to con trol). Therefore, inhibition of nitric oxide synthase by 7-NI resulted in anxiolysis similar to diazepam following acute administration in t he EPM. However, following subchronic administration, unlike diazepam which showed an attenuation of anxiolytic activity, 7-NI displayed enh anced anxiolytic efficacy and was devoid of tolerance. (C) 1998 Elsevi er Science Ltd. All rights reserved.