We have recently demonstrated that various doses of clonidine failed to increase growth hormone (GH) in Fawn-hooded (FH) rats (a rat strain suggested to represent a genetic model of depression). In the present study, we investigated whether long-term antidepressant treatment might normalize clonidine's effect on GH secretion in male FH rats. Long-term (16 days) treatment with the tricyclic antidepressant, imipramine (5 mg/kg/day), the 5-HT uptake inhibiting antidepressant, fluoxetine (2.5 mg/kg/day), and the noradrenergic uptake inhibiting antidepressant, desipramine (5 mg/kg/day), accentuated clonidine's effect on GH levels. On the other hand, long-term treatment with the monoamine oxidase type-A inhibiting antidepressant, clorgyline (1 mg/kg/day) and the alpha 2-noradrenergic antagonists, yohimbine and 1-phenylpiperazine (1 mg/kg/day, each) did not modify clonidine's effect. These findings suggest enhancement of 5-HT2c receptor-mediated function following long-term treatment with uptake inhibiting antidepressants in a genetic animal model of depression.