Ketamine, a rapid-acting antidepressant, has undesirable psychotomimetic effects, including a dissociative effect. There is currently no effective strategy to suppress these side effects while preserving its antidepressant effect. Here, we investigated the effects of a D2/D3 receptor antagonist and partial agonists on the psychotomimetic and antidepressant effects of ketamine in mice and humans. Aripiprazole, a partial agonist, attenuated the psychotomimetic effect, but maintaining and even enhancing the antidepressant-like effect of ketamine in the forced swim test, whereas raclopride, an antagonist, suppressed both effects in mice. Brain-wide Fos mapping and its network analysis suggested the ventral tegmental area (VTA) as a critical region for distinguishing the effects of aripiprazole and raclopride. In the chronic stress model, local infusion of raclopride into the VTA inhibited ketamine's antidepressant-like effect, accompanied by activation of dopaminergic neurons, suggesting the inhibitory effect of VTA activation on the antidepressant-like effect of ketamine. Consistently, systemic injections of raclopride and brexpiprazole, a partial agonist similar to aripiprazole but closer to an antagonist (lower E