Dopamine D2/3 receptor partial agonists failed to produce antidepressant‐like effects in the rat forced swim test

High efficacy, dopamine D3 receptor‐preferring agonists, such as pramipexole, produce antidepressant‐like effects in rodents that are mediated by either a combination of the D2 and D3 receptor subtypes or the D2 receptor alone. Little is known about the antidepressant‐like effects of D2/3 receptor partial agonists; therefore, this study investigated the antidepressant‐like activity of the D3‐preferring partial agonists, BP897, CJ998, and CJ1037, and the mixed action D2 partial agonist aripiprazole in rats. We hypothesized that a D3 partial agonist alone would not be sufficient to produce antidepressant‐like effects. These compounds were evaluated alone and as pretreatments to pramipexole in the rat forced swim test. These compounds produced little, if any, antidepressant‐like activity on their own; however, BP897 and aripiprazole antagonized the antidepressant‐like effects of pramipexole. These data suggest that partial agonist activity at the dopamine D3 and/or D2 receptors is not sufficient to produce antidepressant‐like activity and that partial agonists can block the actions of high efficacy agonists, consistent with receptor theory. Overall, these findings further demonstrate that activation of D2 and D3 receptors with high efficacy agonists is required to produce antidepressant‐like effects in rodents. This work was supported in part by USPHS grants DA020669 and T32 DA07268.