Recent studies have reported antidepressant-like activities of the dopamine D₂/D₃ agonist pramipexole in the chronic mild stress model and in the forced swim test, suggesting that D₃ receptor agonists may represent a new class of antidepressant drugs. However, the relative contribution of D₂ or D₃ receptors to the activity of pramipexole in these models is unclear.

The aim of the current studies was to explore the role of dopamine D₂ and D₃ receptors in the activity of pramipexole in the mouse forced swim test.

The effect of pramipexole (0.1–3.2 mg/kg) in the mouse forced swim test was examined both in conjunction with D₂ and D₃ receptor antagonists (haloperidol (0.1–1 mg/kg) and LU-201640 (A-437203, 5.6–17.8 mg/kg), as well as in D₃ receptor knockout mice obtained on two different background strains (C57BL/6J and B6129SF2/J). Locomotor activity was also assessed following pramipexole administration.

Pramipexole produced dose-dependent reductions in immobility in the forced swim test at doses that did not produce generalized increases in locomotor activity. LU-201640, the D₃ selective antagonist, failed to block the antidepressant-like effects of pramipexole. In contrast, the efficacy of pramipexole in the forced swim test was completely blocked by the D₂ antagonist, haloperidol. No baseline differences were observed between knockout and wild-type mice from either background strain in locomotor activity or in the forced swim test. Furthermore, in both background strains, pramipexole showed similar efficacy in the forced swim test for both wild-type and knockout mice.

Taken together, these studies suggest that the D₂ receptor rather than the D₃ receptor is important for the antidepressant-like activity observed for pramipexole in the mouse forced swim test.