Ketamine-induced NMDA receptor antagonism degrades relational evidence and weakens cautious decision strategies during inferential choices

Background: Decisions often require using learned relationships to guide choices beyond direct experience. This ability can be studied with transitive inference (TI) tasks, in which subjects learn an ordered hierarchy and use it to compare pairs that were not directly experienced before. A phenomenon of TI is the symbolic distance effect (SDE): faster and more accurate choices for pairs with distant rather than similar rank positions in the hierarchy. Pair comparisons require the temporary maintenance of task-relevant information, a cognitive process supported by N-methyl-D-aspartate (NMDA) receptors. Ketamine, an NMDA receptor antagonist, may interfere with the cognitive functions underlying the inferential decision process. Here, we modelled TI decisions using a drift-diffusion model (DDM), representing decision-making as a ramping-to-threshold process, and tested which parameter ketamine influenced. Methods: Two rhesus monkeys performed a TI task based on six items. After reaching the 60% accuracy learning criterion on pairs at SD1 (adjacent ranks), they were tested across all SDs. Testing was conducted under control and sub-anesthetic ketamine conditions at different doses (0.25, 0.50, 0.75 mg/kg). Performance was evaluated by measuring accuracy and latency separately, as well as their relationship, indexed by conditional accuracy functions (CAF). Finally, trial-level data were fitted with DDM. Results: In the control condition, monkeys showed a clear SDE. Ketamine dose-dependently weakened it, reducing the advantage for larger SDs. It also steepened CAF, with a greater loss of accuracy across the RT distribution. DDM showed that behavior was explained by SD-dependent drift and collapsing decision boundaries. Ketamine reduced drift and weakened its modulation by SD, suggesting impaired use of relational evidence. Ketamine also accelerated boundary collapse, which mediated the disruption of the speed-accuracy relationship. Conclusion: DDM showed that ketamine promoted urgency-driven inferential choices based on degraded evidence. These model-derived parameters may help explain decision-making impairments in disorders involving NMDA receptor alterations.