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

The role of the 5-HT2C receptor in mediating active behaviors in the modifi ed rat forced swim test was examined. Three novel selective 5-HT2C receptor agonists, WAY 161503 (0.1-3.0 mg/kg), RO 60-0175 (2-20 mg/kg), and RO 60-0 332 (20 mg/kg), all decreased immobility and increased swimming, a pattern of behavior similar to that which occurs with the selective serotonin reupt ake inhibitor fluoxetine (5-20 mg/kg). However, the prototypical but nonsel ective 5-HT2C receptor agonist m-chlorophenylpiperazine (1-10 mg/kg) increa sed immobility scores in the forced swim test. The selective 5-HT2C recepto r 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 1 61503 (1 mg/kg) and fluoxetine (20 mg/kg). The atypical antidepressant (nor adrenergic alpha (2) and HT2C receptor antagonist) mianserin reduced immobi lity 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 noradre nergic transmission. These data exemplify the benefits of using the modifie d rat forced swim test, which was sensitive to serotonergic compounds and d istinguished behavioral changes associated with serotonergic and noradrener gic effects. Taken together, the results strongly implicate a role for 5-HT 2C receptors in the behavioral effects of antidepressant drugs.