Abstract There is little knowledge regarding the underlying mediating factors for cognitive control at the synaptic level, especially the role played by glutamatergic neurotransmission. In the current study the effect of the NMDA receptor antagonist memantine was examined in a pharmacological fMRI study. Thirty-one healthy adults were scanned twice in a counter-balanced design, either drug naïve or after administration of memantine for 21 days, to build up a steady-state plasma concentration in all participants. The participants performed an auditory attention control task while in the MR scanner. The results showed significant reduction in activation in prefrontal cortex and anterior cingulate cortex after memantine administration compared to the drug naïve session. We suggest that the present results may have implications for the understanding of deficits in cognitive control in psychiatric disorders, like schizophrenia, through altered glutamatergic neurotransmission.