Treatment with pramipexole, a dopamine D(3)/D(2) receptor agonist, reduces depressive symptoms in patients suffering from Parkinson's disease. To test the putative antidepressant quality of pramipexole, its effects were assessed in one of the most attractive animal models of depression, the olfactory bulbectomized (OBX) rat. Two experiments studied the effects of pramipexole on bulbectomy-induced hyperactivity. In experiment I, pramipexole was tested at 0.3 and 1.0 mg/kg together with the reference dopamine D(3) receptor agonist 7-OH-DPAT (0.1 mg/kg) and the tri-cyclic antidepressant imipramine (10 mg/kg). In experiment II, pramipexole was tested at lower doses: 0.03 and 0.1 mg/kg, with the same reference compounds. All animals were tested in the open field on days one (acute), seven (sub-chronic) and fourteen (chronic) of administration, as well as one week after cessation of treatment. Pramipexole, in a U-shaped dose response, reduced bulbectomy-induced hyperactivity after (sub) chronic but not acute administration (like imipramine and 7-OH-DPAT). The highest dose of pramipexole (1.0 mg/kg) did not reduce OBX hyperactivity during treatment. However, one week after cessation of treatment, all pramipexole (including the 1.0 mg/kg dose), 7-OH-DPAT and imipramine groups showed a reduction in OBX-induced hyperactivity. Pramipexole and 7-OH-DPAT exert an antidepressant profile in the OBX-rat model in normalizing bulbectomy-induced hyperactivity during (sub) chronic treatment. Moreover, treatment with both these compounds induced long-lasting changes in the bulbectomized brain similar to established antidepressants, strongly predicting antidepressant activity in major depression.