COMPARISON OF ACUTE AND REPEATED TREATMENT WITH THE 5-HT(1A) RECEPTOR LIGANDS 8-OH-DPAT AND IPSAPIRONE IN ANIMAL-MODELS OF ANXIETY AND DEPRESSION

The present study compared the 5-HT1A receptor ligands 8-OH-DPAT and ipsapirone with diazpepam and imipramine in the shock induced ultrasonic vocalization anxiety test and the forced swimming depression test in the rat. Acutely, 8-OH-DPAT induced anxiolytic and antidepressive effects (ED50: 0.12 and 1.4 mg/kg, i.p., respectively), whereas ipsapirone induced anxiolytic (ED50: 0.6 mg/kg) and moderate antidepressive effects (33% at 3-10 mg/kg). Virtually no tolerance developed for the anxiolytic effects after 2 weeks of treatment with 0.03-1 mg/kg 8-OH-DPAT or 0.1-10 mg/kg ipsapirone (i.p., b.i.d.), with 10 mg/kg/day ipsapirone (s.c., mini-pumps), or with 1.5 mug/rat/hr 8-OH-DPAT (local infusion in the dorsal raphe nucleus, mini-pumps). However, some tolerance developed for the antidepressive effects of 8-OH-DPAT (ED50: 0.6,1.4, 2.5 and >3 mg/kg, after 2 weeks of pretreatment with vehicle, 0.3, 1, and 3 mg/kg 8-OH-DPAT, respectively, i.p., b.i.d.). In the case of ipsapirone, the dose-effect curve in the forced swimming test was shifted to the left after 2 weeks of pretreatment with ipsapirone (0.3-10 mg/kg, i.p., b.i.d.). Acutely, diazepam induced an anxiolytic effect (ED50: 3.6 mg/kg, i.p.), but failed to induce an antidepressive effect; whereas imipramine induced an antidepressive effect (ED50: 20.5 mg/kg) and a moderate anxiolytic effect (max. efficacy: 47% at 30 mg/kg). Upon repeated administration (2 weeks), diazepam (5 mg/kg) showed tolerance for its anxiolytic effects and weak antidepressive effects emerged, whereas imipramine (20 mg/kg) showed weak sensitization for both effects. It is concluded that (a) with all compounds, tolerance, as well as sensitization can be observed, depending on the behavioral test, the dose and the type of compound; and (b) compared with the other compounds tested, relatively low doses of 5-HT1A drugs offer the most attractive profile of mixed anxiolytic/antidepressive activity. (C) 1993 Wiley-Liss, Inc.