A within-subject cognitive battery in the rat: differential effects of NMDA receptor antagonists

The range of cognitive and psychotomimetic effects produced by antagonists of the N-methyl-D-aspartate (NMDA) receptor has lead to widespread usage of these molecules as pharmacological models of cognitive impairment for drug discovery. Historically, NMDA receptor antagonists have been used interchangeably on the assumption that they produce analogous effects.

To profile a subset of these antagonists across a novel within-subject cognitive battery in the rat.

Naïve male Lister Hooded rats were subjected to a series of tests in which they were required to learn a simple visuo-auditory conditional discrimination. They then underwent testing in a delayed discrimination test followed by rule reversal and rule extinction tests.

All NMDA receptor antagonists tested impaired acquisition performance and, with the exception of ketamine and the GluN2A preferring antagonist, NVP-AAM077, impaired consolidation of extinction. GluN2B antagonism produced a singular profile with potentially enhanced delayed discrimination performance and reduced hit rates in the reversal phase. Only PCP (phencyclidine) and ketamine disrupted performance in the delay phase but did so in a delay-independent manner. MK-801, PCP and memantine all increased the hit rate in the reversal phase; whilst only MK-801 and PCP impaired extinction per se.

NMDA receptor-dependent mechanisms are requisite in the acquisition of a simple conditional discrimination and consolidation of extinction. Their role in working memory and reversal tasks appear to be less critical and potentially specific to the paradigm and NMDA receptor antagonist used. It is clearly misleading to generalise across NMDA antagonists with respect to their preclinical cognitive profile.