The nitric oxide synthase inhibitor 7-nitroindazole displays enhanced anxiolytic efficacy without tolerance in rats following subchronic administration

The nitric oxide synthase inhibitor 7-nitroindazole (7-NI) dose-dependently (3.0-30.0 mg/kg) displayed anxiolytic activity, as measured by an increase in open arm exploration time in the elevated plus-maze (EPM), following intraperitoneal (i.p.) administration in rats. Acute administration of 7-NI at 30.0 mg/kg significantly (P < 0.05) increased open arm exploration time by 176% compared to vehicle control, similar to 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 anxiolytic activity at 1.0 mg/kg, as measured by no difference in open arm exploration time compared to vehicle control, while the 3.0 mg/kg dose 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 arm exploration time was observed at 30.0 mg/kg (+ 665% compared to control). Therefore, inhibition of nitric oxide synthase by 7-NI resulted in anxiolysis similar to diazepam following acute administration in the EPM. However, following subchronic administration, unlike diazepam which showed an attenuation of anxiolytic activity, 7-NI displayed enhanced anxiolytic efficacy and was devoid of tolerance.