Modulatory effects of an NMDAR partial agonist in MK-801-induced memory impairment

Acute administration of the N-methyl-d-aspartate (NMDA) non-competitive antagonist, MK-801, impairs novel object recognition (NOR), locomotor activity in open field (OF) and conditioned taste aversion (CTA) in rodents. NMDAR partial agonist d-cycloserine (DCS) reverses these effects in NOR and CTA via modulation of glutamatergic, cholinergic and dopaminergic systems.

To test this hypothesis, we investigated the effects of DCS, a partial NMDAR agonist, on NOR memory, locomotor activity, and CTA memory in Wistar rats on NMDA-glutamate receptor antagonism by MK-801. The potential involvement of dopaminergic and cholinergic systems in improving cognitive functions was explored. MK-801-induced cognitive deficits were assessed using NOR, OF and CTA paradigms. MK-801-induced dopamine release increase in acetylcholinesterase (AChE), mono amine oxidase (MAO) activity and increase in c-fos expression were also investigated.

The effects caused by MK-801 (0.2 mg/kg) were inhibited by administration of the NMDA receptor agonist DCS (15 mg/kg). NOR and CTA paradigms inhibited by MK-801 were attenuated by DCS administration. Moreover, DCS also blocked the MK-801-induced abnormal increase in dopamine content, AChE activity and MAO activity. However, c-fos overexpression was controlled to some extent only.

Based on the NMDAR hypo function hypothesis in some neuropsychiatric disorders, our finding suggests that improving NMDAR hypo function by agonist DCS may play a significant role.