Antidepressant-like behavioral effects mediated by 5-hydroxytryptamine(2C) receptors

The role of the 5-HT(2C) receptor in mediating active behaviors in the modified rat forced swim test was examined. Three novel selective 5-HT(2C) receptor agonists, WAY 161503 (0.1-3.0 mg/kg), RO 60-0175 (2-20 mg/kg), and RO 60-0332 (20 mg/kg), all decreased immobility and increased swimming, a pattern of behavior similar to that which occurs with the selective serotonin reuptake inhibitor fluoxetine (5-20 mg/kg). However, the prototypical but nonselective 5-HT(2C) receptor agonist m-chlorophenylpiperazine (1-10 mg/kg) increased immobility scores in the forced swim test. The selective 5-HT(2C) receptor antagonist SB 206533 was inactive when given alone (1-20 mg/kg). However, SB 206533 (20 mg/kg) blocked the antidepressant-like effects of both WAY 161503 (1 mg/kg) and fluoxetine (20 mg/kg). The atypical antidepressant (noradrenergic α₂ and 5-HT(2C) receptor antagonist) mianserin reduced immobility and increased climbing at 30 mg/kg. At a behaviorally subactive dose (10 mg/kg), mianserin abolished the effects of WAY 161503 (1 mg/kg) on both swimming and immobility scores. Mianserin blocked the effects of fluoxetine (20 mg/kg) on swimming only; mianserin plus fluoxetine reduced immobility and induced a switch to climbing behavior, suggesting activation of noradrenergic transmission. These data exemplify the benefits of using the modified rat forced swim test, which was sensitive to serotonergic compounds and distinguished behavioral changes associated with serotonergic and noradrenergic effects. Taken together, the results strongly implicate a role for 5-HT(2C) receptors in the behavioral effects of antidepressant drugs.