Measure of anxiety-related behaviors and hippocampal BDNF levels associated to the amnesic effect induced by MK-801 evaluated in the modified elevated plus-maze in rats.

Non-competitive N-methyl-d-aspartate receptor (NMDA-R) antagonists impair rodent cognition. Specifically, MK-801, the most potent NMDA-R antagonist, induces an amnesic effect on the modified elevated plus maze (mEPM) learning test in rodents, which reflects spatial long-term memory. However, alterations in anxiety-related behaviors could overlap this amnesic effect. Accumulated evidence supports the role of brain-derived neurotrophic factor (BDNF) in learning and memory processes and deficits in hippocampal BDNF function, which underlie cognitive impairments, have been extensively reported. Therefore, we investigated if changes in anxiety-related behaviors and hippocampal BDNF levels are related with the amnesic effect induced by MK-801 in the mEPM.Transfer latency (TL) as an index of spatial memory in the mEPM was used. TL1 was evaluated 30 min after saline/MK-801 injection (day 1, acquisition session) while learning/memory performance was measured 24 h later at TL2 (day 2, retention session). Also at TL2, two other experimental groups were added to measure the anxiety-related behaviors using the classic EPM and BDNF protein levels by ELISA. To evaluate if amnesia endures, an additional session was recorded on day 3 (TL3) and BDNF levels were measured.While TL1 was not significantly modified by MK-801, TL2 was increased compared to the control group indicating an amnesic effect. This effect was not mimicked by anxiety-related behaviors and it was associated to a significant attenuation of BDNF levels. During the third post-training day, the cognitive performance of MK-801-treated animals was improved and an increased BDNF protein expression in the hippocampus accompanied this change

Prefrontal cortex lesions cause only minor effects on the hyperlocomotion induced by MK-801 and its reversal by clozapine.

The non-competitive NMDA receptor antagonist MK-801 elicits a behavioural syndrome in rodents characterized by hyperlocomotion and stereotypies, which is antagonized by antipsychotic drugs. NMDA receptor antagonists increase prefrontal cortex (PFC) activity in rodents, as assessed by electrophysiological and neurochemical measures. The increase in glutamate outflow induced by systemic MK-801 administration in the medial PFC (mPFC) is prevented by the local administration of clozapine (Clz). In the present study, we examine whether a PFC lesion alters the behavioural syndrome induced by MK-801 in rats and the Clz-induced antagonism of MK-801 actions. We evaluated the hyperlocomotion, stereotypies and other behavioural changes induced by MK-801 in the open field and the effect of electrolytic lesions of the mPFC, and of cortical transection on the behavioural syndrome induced by MK-801 and its reversal by Clz. MK-801 (0.1-0.2 mg/kg i.p.) reduced rearings but only the higher dose induced hyperlocomotion. At this dose, MK-801 also increased disorganized movements, head weavings, and induced ataxia signs. An electrolytic lesion of the mPFC markedly reduced the number of rearings pre-treatment but caused a very slight attenuation of MK-801-induced hyperlocomotion. Cortical transection did not significantly alter MK-801 effects. Clz administration (1 mg/kg s.c.) significantly attenuated hyperlocomotion, head weavings and ataxia signs induced by MK-801 but did not prevent the decrease in rearings. The effect of Clz was essentially unaffected by electrolytic lesions of the mPFC. These results show that MK-801-induced motor syndrome and its reversal by Clz are mostly independent on PFC integrity.