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Abstract Aim The therapeutic potential of N‐methyl‐D‐aspartate glutamate receptor (NMDAR) antagonists, particularly ketamine, in mood disorders, is linked to their modulation of dopamine dynamics in the medial prefrontal cortex (mPFC). However, conflicting effects of distinct NMDAR antagonists, like ketamine and phencyclidine, on mPFC dopamine levels stem from variances in their receptor affinity profiles. This study investigates the impact of intermittent subchronic administration of an NMDAR antagonist on dopamine synthesis capacity and responsiveness within the mPFC, focusing on Dizocilpine (MK‐801), a highly selective NMDAR antagonist. Methods In vivo microdialysis and high‐performance liquid chromatography assessed extracellular dopamine levels in the mPFC following subchronic MK‐801 treatment. Locomotor activity was measured using a computed video tracking system. Results Intermittent subchronic MK‐801 administration, followed by a 24‐h withdrawal, preserved both dopamine synthesis capacity and responsiveness to MK‐801 challenge in the mPFC. However, altered locomotor activity was observed, deviating from previous findings indicating impaired dopamine synthesis and responsiveness in the mPFC with twice‐daily subchronic NMDAR antagonist treatment. Conclusion These findings offer crucial biochemical insights into the diverse impacts of NMDAR antagonists on dopamine dynamics and the distinct therapeutic mechanisms associated with ketamine in depression treatment. However, further investigation is imperative to pinpoint potential inconsistencies stemming from variances in drug type, dosage, or administration frequency.