Dopamine D2/D3 receptor agonists produce antidepressant‐like effects in the rat forced swim test through co‐activation of both receptor subtypes

Dopamine D2/D3 receptor agonists have been shown to have antidepressant actions in clinical and preclinical studies; however, the dopamine receptor subtype that mediates the antidepressant effects is unknown. The present study investigated the antidepressant‐like effects of dopamine D1‐, D2‐, D3‐, and D4‐preferring agonists in the rat forced swim test and the role of different dopamine receptor subtypes in these behavioral effects. The dopamine D3‐preferring agonists (PD‐128,907, pramipexole, quinpirole, and apomorphine), the D2‐preferring agonist (sumanirole), and the dopamine D1 agonist (SKF81297), but not the D4 agonist (ABT‐724), decreased immobility in the forced swim test, indicating an antidepressant profile of action. The D2 antagonist L‐741,626 and the D3 antagonist PGO1037, but not the D1 antagonist SCH23390, attenuated the antidepressant effects of the D2/D3 agonists. These data suggest that antidepressant actions of dopamine D2/D3 agonists require the activation of both D2 and D3 receptor subtypes and blockade of either receptor subtype eliminates the antidepressant effects. This work was supported by USPHS grants DA00254, DA020669, T32 GM07767, T32 DA07267, and T32 DA07268.