The NMDAr antagonist ketamine interferes with manipulation of information for transitive inference reasoning in non-human primates

Abstract

One of the most remarkable traits of highly encephalized animals is their ability to manipulate knowledge flexibly to infer logical relationships. Operationally, the corresponding cognitive process can be defined as reasoning. One hypothesis is that this process relies on the reverberating activity of glutamate neural circuits, sustained by NMDA receptor (NMDAr) mediated synaptic transmission, in both parietal and prefrontal areas. We trained two macaque monkeys to perform a form of deductive reasoning - the transitive inference task - in which they were required to learn the relationship between six adjacent items in a single session and then deduct the relationship between nonadjacent items that had not been paired in the learning phase. When the animals had learned the sequence, we administered systemically a subanaesthetic dose of ketamine (a NMDAr antagonist) and measured their performance on learned and novel problems. We observed impairments in determining the relationship between novel pairs of items. Our results are consistent with the hypothesis that transitive inference premises are integrated during learning in a unified representation and that reducing NMDAr activity interferes with the use of this mental model, when decisions are required in comparing pairs of items that have not been learned.

Keywords: NMDA receptors; Transitive inference; ketamine; symbolic distance.