The NMDA receptor antagonist MK-801 disrupts auditory-guided behavior through sex-dependent response channels in an operant oddball task

Schizophrenia involves marked deficits in sensory-guided behavior, yet the behavioral consequences of N-methyl-D-aspartate (NMDA) receptor hypofunction for auditory decision-making, and whether they differ by sex, remain unclear. We trained female and male rats on an operant auditory oddball task requiring responses to rare deviant tones (go context) while withholding responses to frequent standard tones (no-go context) across three inter-stimulus intervals (ISIs), and tested performance after a single dose of the NMDA receptor antagonist MK-801 using signal detection theory. We subcutaneously injected MK-801 (0.1 mg/kg; 0.075 mg/ml) to generate the drug-induced group, and saline solution 0.9% to produce the control group, across female and male rats. MK-801 reduced discrimination sensitivity, but through sex-dependent response channels. In females, the deficit was carried mainly by reduced correct detections of deviant tones, alongside a more conservative response criterion. In males, the sensitivity loss was weaker and ISI-dependent but was accompanied by increased false alarms to standard tones and faster false-alarm responses, indicating diminished response withholding. These effects were most pronounced at the longer ISIs and were expressed as immediate post-injection shifts rather than progressive session-by-session drift. We quantified all effects with linear mixed-effects models and Holm-corrected planned contrasts. Together, these findings show that acute administration of the NMDA receptor blockade disrupts auditory-guided behavior through dissociable, sex-specific response channels, providing a behavioral framework relevant to abnormalities associated with schizophrenia.