Antidepressant-like activity of 5-HT_1A agonists measured with the forced swim test

This study examined the abilities of 5-hydroxytryptamine (5-HT) agonists with varying selectivity for different subtypes of 5-HT receptors to produce antidepressant-like behavioral effects in the forced swim test in rats. The 5-HT_1A agonists 8-OH-DPAT (0.125-1.0 mg/kg, SC) and tandospirone (SM-3997) (5-20 mg/kg, SC) both produced dose-related decreases in immobility time following subchronic treatment in rats. These effects were similar to those of the tricyclic antidepressants imipramine (5-15 mg/kg) and desipramine (5-15 mg/kg). In addition, the 5-HT_1A agonists, buspirone (20 mg/kg), gepirone (20 mg/kg) and ipsapirone (10 and 20 mg/kg) demonstrated antidepressant-like effects. Other groups of rats treated subchronically with each of the 5-HT_1A agonists or antidepressants showed no increase in locomotor activity, so that general changes in activity could not account for the reduction of immobility time in the forced swim test. 5-HT agonists selective for other receptor subtypes, such as the 5-HT_1B/1C agonist m-CPP (5 mg/kg) and the 5-HT_2/1C agonist DOB (1 mg/kg), were not effective in this behavioral test. The benzodiazepine diazepam (5 mg/kg) also failed to reduce immobility time, suggesting that anxiolytic properties of 5-HT_1A agonists did not mediate this behavioral effect. A common metabolite of some of the 5-HT_1A agonists, 1-PP, was ineffective in reducing immobility time. The stimulant d-amphetamine (2 mg/kg) significantly reduced immobility time but also significantly increased locomotor activity. Pretreatment with the 5-HT synthesis inhibitor PCPA alone did not alter immobility time, and did not alter the antidepressant-like effects of 8-OH-DPAT or tandospirone, suggesting that the 5-HT_1A agonists are producing their antidepressant-like effects through postsynaptic 5-HT_1A receptors. These results suggest that 5-HT_1A agonists may have antidepressant efficacy and act as a novel class of antidepressant drug.