Acute MK-801 Research Articles

Development of the MAM model of schizophrenia in mice: Sex similarities and differences of hippocampal and prefrontal cortical function

Schizophrenia is a debilitating disorder with complex and unclarified etiological factors. Sex differences have been observed in humans but animal models have only focused on male subjects. In this study, we report the establishment of the neurodevelopmental MAM model of schizophrenia in mice and compare the schizotypic-like characteristics and cognitive functions in both sexes. Pregnant mice were injected with methylazoxymethanol acetate (MAM) or saline on gestational day (GD) 16 (MAM-16) or 17 (MAM-17). Female MAM-16, but not MAM-17 treated mice exhibited enhanced hyperlocomotion after acute MK-801 administration, compared to saline treated mice. Male MAM-16, but not MAM-17, treated mice showed reduced pre-pulse inhibition of the acoustic startle reflex. Both male and female MAM-16 and MAM-17 treated mice exhibited smaller hippocampal (HPC) size and thinning of the prefrontal cortex (PFC), but only male MAM-16 treated mice showed decreased parvalbumin expression in HPC and PFC. Similarly, both male and female MAM-16 treated mice displayed impaired contextual fear memory and significantly reduced long-term potentiation (LTP) in the HPC CA1 synapses. However, male, but not female, MAM-16 treated mice exhibited deficits in the delayed alternation task and LTP in layer II PFC synapses. Proteomic analyses of PFC lysates further showed significant MAM- and sex-dependent differences in protein expression regulation. Our results demonstrate that while both male and female mice, prenatally exposed to MAM on GD16, display several core schizophrenia-like deficits and impairments in the hippocampus, only male MAM-treated mice have PFCdependent cognitive deficits.

Effects of chronic prenatal MK-801 treatment on object recognition, cognitive flexibility, and drug-induced locomotor activity in juvenile and adult rat offspring

BackgroundPatients with schizophrenia display impaired cognitive functioning and increased sensitivity to psychomimetic drugs. The neurodevelopmental hypothesis of schizophrenia posits that disruption of the developing brain predisposes neural networks to lasting structural and functional abnormalities resulting in the emergence of such symptoms in adulthood. Given the critical role of the glutamatergic system in early brain development, we investigated whether chronic prenatal exposure to the glutamate NMDA receptor antagonist, MK-801, induces schizophrenia-like behavioural and neurochemical changes in juvenile and adult rats. MethodsPregnant Long–Evans rats were administered saline or MK-801 (0.1mg/kg; s.c.) at gestation day 7–19. Object recognition memory and cognitive flexibility were assessed in the male offspring using a novel object preference task and a maze-based set-shifting procedure, respectively. Locomotor-activating effects of acute amphetamine and MK-801 were also assessed. ResultsAdult, but not juvenile, prenatally MK-801-treated rats failed to show novel object preference after a 90min delay, suggesting that object recognition memory may have been impaired. In addition, the set-shifting task revealed impaired acquisition of a new rule in adult prenatally MK-801-treated rats compared to controls. This deficit appeared to be driven by regression to the previously learned behaviour. There were no significant differences in drug-induced locomotor activity in juvenile offspring or in adult offspring following acute amphetamine challenges. Unexpectedly, MK-801-induced locomotor activity in adult prenatally MK-801-treated rats was lower compared to controls. ConclusionsGlutamate transmission dysfunction during early development may modify behavioural parameters in adulthood, though these parameters do not appear to model deficits observed in schizophrenia.

Dissociable effects of the d- and l- enantiomers of govadine on the disruption of prepulse inhibition by MK-801 and apomorphine in male Long-Evans rats.

The search for novel antipsychotic drugs to treat schizophrenia is driven by the poor treatment efficacy, serious side effects, and poor patient compliance of current medications. Recently, a class of compounds known as tetrahydroprotoberberines, which includes the compound d,l-govadine, have shown promise in preclinical rodent tests relevant to schizophrenia. To date, the effect of govadine on prepulse inhibition (PPI), a test for sensorimotor gating commonly used to assess the effects of putative treatments for schizophrenia, has not been determined. The objective of the present study was to determine the effects of each enantiomer of govadine (d- and l-govadine) on PPI alone and its disruption by the distinct pharmacological compounds apomorphine and MK-801. Male Long-Evans rats were treated systemically with d- or l-govadine and apomorphine or MK-801 prior to PPI. The PPI paradigm employed here included parametric manipulations of the prepulse intensity and the interval between the prepulse and pulse. Acute MK-801 (0.15mg/kg) significantly increased the startle response to startle pulses alone, while both MK-801 and apomorphine (0.2mg/kg) significantly increased reactivity to prepulse-alone trials. Both MK-801 and apomorphine disrupted PPI. In addition, d-govadine alone significantly disrupted PPI in the apomorphine experiment. Pretreatment with l-, but not d-, govadine (1.0mg/kg) blocked the effect of apomorphine and MK-801 on PPI. Treatment of rats with l-govadine alone (0.3, 1.0, 3.0mg/kg) also dose-dependently increased PPI. Given the high affinity of l-govadine for dopamine D2 receptors, these results suggest that further testing of l-govadine as an antipsychotic is warranted.

Risperidone reverses the spatial object recognition impairment and hippocampal BDNF-TrkB signalling system alterations induced by acute MK-801 treatment.

The aim of the present study was to investigate the effects of a commonly-used atypical antipsychotic, risperidone, on alterations in spatial learning and in the hippocampal brain-derived neurotrophic factor (BDNF)-tyrosine receptor kinase B (TrkB) signalling system caused by acute dizocilpine maleate (MK-801) treatment. In experiment 1, adult male Sprague-Dawley rats subjected to acute treatment of either low-dose MK801 (0.1 mg/kg) or normal saline (vehicle) were tested for spatial object recognition and hippocampal expression levels of BDNF, TrkB and the phophorylation of TrkB (p-TrkB). We found that compared to the vehicle, MK-801 treatment impaired spatial object recognition of animals and downregulated the expression levels of p-TrkB. In experiment 2, MK-801- or vehicle-treated animals were further injected with risperidone (0.1 mg/kg) or vehicle before behavioural testing and sacrifice. Of note, we found that risperidone successfully reversed the deleterious effects of MK-801 on spatial object recognition and upregulated the hippocampal BDNF-TrkB signalling system. Collectively, the findings suggest that cognitive deficits from acute N-methyl-D-aspartate receptor blockade may be associated with the hypofunction of hippocampal BDNF-TrkB signalling system and that risperidone was able to reverse these alterations.

Acute systemic MK-801 induced functional uncoupling between hippocampal areas CA3 and CA1 with distant effect in the retrosplenial cortex

The hippocampus and retrosplenial cortex are integrated within a higher-order cognitive circuit supporting relational (spatial, contextual, episodic) forms of learning and memory. Hippocampal place cells can coordinate multiple parallel representations in the same physical environment. Novel environment exploration triggers expression of immediate-early genes (IEGs) Arc and Homer1a in spatial context-specific ensembles of CA1 and CA3 neurons. Less is know about ensemble coding in the retrosplenial cortex (RSC), a region directly connected and functionally coupled to CA1. Hippocampal and retrosplenial damage is found in patients with schizophrenia alongside cognitive deficits affecting relational memory. Systemic administration of non-competitive NMDAR antagonists such as MK-801 is used to model psychosis in animals and humans. Acute systemic MK-801 (0.15 mg/kg) impaired cognitive control in rats and ensemble code for spatial context in CA1. Here, we use expression of immediate-early genes Arc and Homer 1a to examine ensemble coding in rat CA3 and RSC to test if the effect of MK-801 extends upstream and downstream of CA1, respectively. Different rats explored the same context twice (A/A), explored two distinct contexts (A/B) or remained in their home cage (CC). In contrast to CA1, MK-801 did not affect ensemble coding in CA3. Unlike CA3 and CA1, similarity of RSC ensembles active during exploration did not reflect change in spatial context, but MK-801 (0.15 mg/kg) increased similarity in RSC ensembles active during spontaneous behavior in the home cage. The data provide support for MK-801-induced functional uncoupling between CA3 and CA1 and suggest that ensemble coding deficit may extend downstream of CA1. This deficit may reflect hyperassociative state in the cognitive circuit underlying cognitive disorganization in psychosis. © 2016 Wiley Periodicals, Inc.

MK-801-induced impairments on the trial-unique, delayed nonmatching-to-location task in rats: effects of acute sodium nitroprusside.

The cognitive symptoms observed in schizophrenia are not consistentlyalleviated by conventional antipsychotics. Following a recent pilot study, sodium nitroprusside (SNP) has been identified as a promising adjunct treatment to reduce the working memory impairments experienced by schizophrenia patients. The present experiments were designed to explore the effects of SNP on the highly translatable trial-unique, delayed nonmatching-to-location (TUNL) task in rats with and without acute MK-801 treatment. SNP (0.5, 1.0, 2.0, 4.0, and 5.0mg/kg) and MK-801 (0.05, 0.075, and 0.1mg/kg) were acutely administered to rats trained on the TUNL task. Acute MK-801 treatment impaired TUNL task accuracy. Administration of SNP (2.0mg/kg) with MK-801 (0.1mg/kg) failed to rescue performance on TUNL. SNP (5.0mg/kg) administration nearly 4h prior to MK-801 (0.05mg/kg) treatment had no preventative effect on performance impairments. SNP (2.0mg/kg) improved performance on a subset of trials. These results suggest that SNP may possess intrinsic cognitive-enhancing properties but is unable to block the effects of acute MK-801 treatment on the TUNL task. These results are inconsistent with the effectiveness of SNP as an adjunct therapy for working memory impairments in schizophrenia patients. Future studies in rodents that assess SNP as an adjunct therapy will be valuable in understanding the mechanisms underlying the effectiveness of SNP as a treatment for schizophrenia.

The Influence of the CB1 Receptor Ligands on the Schizophrenia-Like Effects in Mice Induced by MK-801.

A growing body of psychiatric research has emerged, focusing on the role of endocannabinoid system in psychiatric disorders. For example, the endocannabinoid system, via cannabinoid CB (CB1 and CB2) receptors, is able to control the function of many receptors, such as N-methyl-d-aspartate (NMDA) receptors connected strictly with psychosis or other schizophrenia-associated symptoms. The aim of the present research was to investigate the impact of the CB1 receptor ligands on the symptoms typical for schizophrenia. We provoked psychosis-like effects in mice by an acute administration of NMDA receptor antagonist, MK-801 (0.1–0.6 mg/kg). An acute administration of MK-801 induced psychotic symptoms, manifested in the increase in locomotor activity (hyperactivity), measured in actimeters, as well as the memory impairment, assessed in the passive avoidance task. We revealed that an acute injection of CB1 receptor agonist, oleamide (5–20 mg/kg), had no influence on the short- and long-term memory-related disturbances, as well as on the hyperlocomotion in mice, provoking by an acute MK-801. In turn, an amnestic effects or hyperactivity induced by an acute MK-801 was attenuated by an acute administration of AM 251 (0.25–3 mg/kg), a CB1 receptor antagonist. The present findings confirm that endocannabinoid system is able to modify a variety of schizophrenia-like responses, including the cognitive disturbances and hyperlocomotion in mice. Antipsychotic-like effects induced by CB1 receptor antagonist, obtained in our research, confirm the potential effect of CB1 receptor blockade and could have important therapeutic implications on clinical settings, in the future.

Effects of the metabotropic glutamate receptor 5 positive allosteric modulator CDPPB on rats tested with the paired associates learning task in touchscreen-equipped operant conditioning chambers

Effective treatments for the cognitive symptoms of schizophrenia are critically needed. Positive allosteric modulation (PAM) of metabotropic glutamate receptor subtype 5 (mGluR5) is one strategy currently under investigation to improve these symptoms. Examining cognition using touchscreen-equipped operant chambers may increase translation between preclinical and clinical research through analogous behavioral testing paradigms in rodents and humans. We used acute CDPPB (1–30mg/kg) treatment to examine the effects of mGluR5 PAM in the touchscreen paired associates learning (PAL) task using well-trained rats with and without co-administration of acute MK-801 (0.15mg/kg). CDPPB had no consistent effects on task performance when administered alone and failed to reverse the MK-801 induced impairments at any of the examined doses. Overall, the disruptive effects of MK-801 on PAL were consistent with previous research but increasing mGluR5 signaling is not beneficial in the PAL task. Future research should test whether administration of CDPPB during PAL acquisition increases performance.

Effects of D- and L-govadine on the disruption of touchscreen object-location paired associates learning in rats by acute MK-801 treatment.

New pharmacological treatments for the cognitive deficits in schizophrenia are needed. Tetrahydroprotoberberines, such as govadine, are one class of compounds with dopaminergic activities that may be useful in treating some aspects of the cognitive symptoms of the disorder. The objective of the present studies was to test the effects of the D- and L-enantiomers of govadine on the impairment in a paired-associate learning (PAL) task produced by acute MK-801 in rats. We also assessed effects of the typical antipsychotic haloperidol as a comparator compound. MK-801 (0.05, 0.1, 0.15, and 0.2 mg/kg), D- and L-govadine (0.3, 1.0, and 3.0 mg/kg), and haloperidol (0.05, 0.1, and 0.25 mg/kg) were administered acutely to rats well trained on the PAL task in touchscreen-equipped operant conditioning chambers. Acute MK-801 impaired performance of PAL in a dose-dependent manner by reducing accuracy and increasing correction trials. L-Govadine (1.0 mg/kg), but not D-govadine, blocked the disruptive effects of MK-801 (0.15 mg/kg) on PAL. Haloperidol failed to affect the MK-801-induced disruption of PAL. Higher doses of L-govadine and haloperidol dramatically impaired performance of the task which confounded interpretation of cognitive outcomes. L-Govadine appears unique in its ability to improve performance of the MK-801-induced impairment in the PAL task. This behavioral effect may relate the ability of L-govadine to antagonize dopamine D2 receptors while also promoting dopamine efflux. Future research should further characterize the role of the dopamine system in the rodent PAL task to elucidate the mechanisms of its pro-cognitive effects.

MK-801 treatment affects glycolysis in oligodendrocytes more than in astrocytes and neuronal cells: insights for schizophrenia.

Schizophrenia is a debilitating mental disorder, affecting more than 30 million people worldwide. As a multifactorial disease, the underlying causes of schizophrenia require analysis by multiplex methods such as proteomics to allow identification of whole protein networks. Previous post-mortem proteomic studies on brain tissues from schizophrenia patients have demonstrated changes in activation of glycolytic and energy metabolism pathways. However, it is not known whether these changes occur in neurons or in glial cells. To address this question, we treated neuronal, astrocyte, and oligodendrocyte cell lines with the NMDA receptor antagonist MK-801 and measured the levels of six glycolytic enzymes by Western blot analysis. MK-801 acts on the glutamatergic system and has been proposed as a pharmacological means of modeling schizophrenia. Treatment with MK-801 resulted in significant changes in the levels of glycolytic enzymes in all cell types. Most of the differences were found in oligodendrocytes, which had altered levels of hexokinase 1 (HK1), enolase 2 (ENO2), phosphoglycerate kinase (PGK), and phosphoglycerate mutase 1 after acute MK-801 treatment (8 h), and HK1, ENO2, PGK, and triosephosphate isomerase (TPI) following long term treatment (72 h). Addition of the antipsychotic clozapine to the cultures resulted in counter-regulatory effects to the MK-801 treatment by normalizing the levels of ENO2 and PGK in both the acute and long term cultures. In astrocytes, MK-801 affected only aldolase C (ALDOC) under both acute conditions and HK1 and ALDOC following long term treatment, and TPI was the only enzyme affected under long term conditions in the neuronal cells. In conclusion, MK-801 affects glycolysis in oligodendrocytes to a larger extent than neuronal cells and this may be modulated by antipsychotic treatment. Although cell culture studies do not necessarily reflect the in vivo pathophysiology and drug effects within the brain, these results suggest that neurons, astrocytes, and oligodendrocytes are affected differently in schizophrenia. Employing in vitro models using neurotransmitter agonists and antagonists may provide new insights about the pathophysiology of schizophrenia which could lead to a novel system for drug discovery.

Effects of NMDA and GABA-A Receptor Antagonism on Auditory Steady-State Synchronization in Awake Behaving Rats.

Background:The auditory steady-state response, which measures the ability of neural ensembles to entrain to rhythmic auditory stimuli, has been used in human electroencephalogram studies to assess sensory processing and electrical oscillatory deficits. Patients with schizophrenia show a deficit in auditory steady-state response at 40 Hz, and therefore this may be a useful biomarker to study this disorder.Methods:We used auditory steady-state response recordings from the primary auditory cortex, hippocampus, and vertex electroencephalogram sites in awake behaving rats to determine whether pharmacological impairment of excitatory or inhibitory neurotransmission mimics auditory steady-state response abnormalities in schizophrenia.Results:We found the most robust response to auditory stimuli in the primary auditory cortex, in line with previous studies suggesting this region is the primary generator of the auditory steady-state response in humans. Acute MK-801 (0.1mg/kg i.p.) increased primary auditory cortex intertrial coherence during auditory steady-state response at 20 and 40 Hz. Chronic MK-801 (21-day exposure at this daily dose) had no significant effect on 40-Hz auditory steady-state response. Furthermore, we found no effect of acute or chronic picrotoxin (a GABA-A antagonist) on intertrial coherence.Conclusions:Our data indicate that acute N-methyl-d-aspartate receptor antagonism increases synchronous activity in the primary auditory cortex in a frequency-specific manner, supporting the widely held view that acute N-methyl-d-aspartate antagonism augments gamma oscillations. Thus, rodent auditory steady-state response could be a valuable method to study the cortical ability to support synchronous activity at specific frequencies.

DNA microarray unravels rapid changes in transcriptome of MK-801 treated rat brain.

To investigate the impact of MK-801 on gene expression patterns genome wide in rat brain regions. Rats were treated with an intraperitoneal injection of MK-801 [0.08 (low-dose) and 0.16 (high-dose) mg/kg] or NaCl (vehicle control). In a first series of experiment, the frontoparietal electrocorticogram was recorded 15 min before and 60 min after injection. In a second series of experiments, the whole brain of each animal was rapidly removed at 40 min post-injection, and different regions were separated: amygdala, cerebral cortex, hippocampus, hypothalamus, midbrain and ventral striatum on ice followed by DNA microarray (4 × 44 K whole rat genome chip) analysis. Spectral analysis revealed that a single systemic injection of MK-801 significantly and selectively augmented the power of baseline gamma frequency (30-80 Hz) oscillations in the frontoparietal electroencephalogram. DNA microarray analysis showed the largest number (up- and down- regulations) of gene expressions in the cerebral cortex (378), midbrain (376), hippocampus (375), ventral striatum (353), amygdala (301), and hypothalamus (201) under low-dose (0.08 mg/kg) of MK-801. Under high-dose (0.16 mg/kg), ventral striatum (811) showed the largest number of gene expression changes. Gene expression changes were functionally categorized to reveal expression of genes and function varies with each brain region. Acute MK-801 treatment increases synchrony of baseline gamma oscillations, and causes very early changes in gene expressions in six individual rat brain regions, a first report.

Strain-dependent differential behavioral responses of zebrafish larvae to acute MK-801 treatment

The zebrafish is a relatively new model organism and has become a valuable tool in genetic, developmental, and pharmacological researches. Zebrafish larvae, compared with adult, are particularly suitable for high-throughput screening of drug effects. AB and TU are well established in-bred zebrafish strains. The behavioral responses to acute MK-801 treatments (0, 5, 20, 100, and 200μM) under illumination at 50lx were studied using zebrafish larvae of both AB and TU strains at 7dpf with ZebraLab software. Two behavioral parameters, traveling distance and activity counts, were analyzed. “Traveling distance” represents locomotor activity, whereas “activity count” is any activity including small, non-ambulatory movements. Zebrafish larvae of TU strain demonstrated inhibitory effects in both behavioral parameters in response to MK-801 treatment. Zebrafish larvae of AB strain showed lack of responses to MK-801 treatments in traveling distance, and showed increases in activity counts. Therefore, zebrafish larvae of AB and TU strains demonstrated opposite responses in activity counts towards MK-801 treatment. Differences in the level of neurotransmitters and their respective metabolites (NE and MHPG, DA and DOPAC, 5-HT and 5-HIAA) between AB and TU strain zebrafish larvae were discovered by HPLC analysis, which was related to the strain-dependent differential behavioral responses to MK-801 treatment. Conclusion: Under the influences of MK-801, in contrast with TU strain, AB strain zebrafish larvae demonstrated activity changes similar to previous studies on rodents. AB strain larvae are better model organisms than TU strain larvae in MK-801 related behavioral studies.

Reverse translation of clinical electrophysiological biomarkers in behaving rodents under acute and chronic NMDA receptor antagonism.

Electroencephalogram (EEG) stands out as a highly translational tool for psychiatric research, yet rodent and human EEG are not typically obtained in the same way. In this study we developed a tool to record skull EEG in awake-behaving rats in a similar manner to how human EEG are obtained and then used this technique to test whether acute NMDA receptor antagonism alters rodent EEG signals in a similar manner as in humans. Acute MK-801 treatment elevated gamma power and reduced beta band power, which closely mirrored EEG data from healthy volunteers receiving acute ketamine. To explore the mechanisms behind these oscillatory changes, we examined the effects of GABA-A receptor blockade, finding that picrotoxin (PTX) recapitulated the decrease in sound-evoked beta oscillations observed with acute MK-801, but did not produce changes in gamma band power. Chronic treatment with either PTX or MK-801 did not affect frequency-specific oscillatory activity when tested 24 h after the last drug injection, but decreased total broadband oscillatory power. Overall, this study validated a novel platform for recording rodent EEG and demonstrated similar oscillatory changes after acute NMDA receptor antagonism in both humans and rodents, suggesting that skull EEG may be a powerful tool for further translational studies.

Effects of an α5GABAA inverse agonist on MK-801-induced learning deficits in an incremental repeated acquisition task.

N-methyl-D-aspartate receptors (NMDARs) are essential for several kinds of synaptic plasticity and play a critical role in learning and memory. Deficits in NMDAR functioning may be partially responsible for the learning and memory deficits associated with aging and numerous diseases. Administration of MK-801, a noncompetitive NMDAR antagonist, is commonly used as a preclinical model of NMDAR dysfunction. The objective of this study was to assess the effects of α5GABAA receptor inhibition on learning deficits in the incremental repeated acquisition (IRA) task induced by acute MK-801 administration. The IRA task, commonly used to examine factors that affect learning, begins with a single response and increments to progressively longer chains throughout a single session as behavior meets preset criteria. MK-801 (0.03-0.5 mg/kg, intraperitoneally), administered 10 min pretesting, produced a significant dose-dependent decrease in measures of IRA performance at doses greater than or equal to 0.25 mg/kg. The MK-801-induced deficit was attenuated after treatment with an α5GABAA receptor inverse agonist, L-655,708 (1 mg/kg, intraperitoneally). The present study provides the focus for, and supports the feasibility of, further in-depth definitive studies examining α5GABAA receptor inhibition as a suitable candidate for the attenuation of NMDAR-related deficits.

MK-801-induced and scopolamine-induced hyperactivity in rats neonatally treated chronically with MK-801

This study investigated the effects of chronic neonatal blockade of N-methyl-D-aspartate (NMDA) receptors on NMDA and muscarinic acetylcholine receptor-mediated neurotransmission in adulthood. Rats neonatally treated chronically with MK-801/saline were tested for 40 min, at the age of 14-16 weeks, for locomotor activity in an open field immediately after acute administration of MK-801 (0.2 mg/kg) or scopolamine (0.4-2.0 mg/kg). Rats neonatally treated with MK-801 showed significantly higher locomotor activity than those treated with saline. Acute MK-801 administration caused hyperlocomotion regardless of neonatal treatment, but the effect was more potent in rats neonatally treated with MK-801. In contrast, acute scopolamine administration did not cause hyperlocomotion in rats neonatally treated with saline, but significantly increased locomotion in those neonatally treated with MK-801. The results suggest that chronic neonatal NMDA receptor blockade causes changes in glutamatergic and cholinergic transmission in adulthood long after the cessation of treatment.

Neonatal MK-801 treatment differentially alters the effect of adolescent or adult MK-801 challenge on locomotion and PPI in male and female rats

Schizophrenia is a neurodevelopmental disorder and is typically "triggered" by subsequent insults in life. The N-methyl-D-aspartate (NMDA) receptor antagonist dizocilpine (MK-801) induces locomotor hyperactivity and prepulse inhibition (PPI) deficits, which can mimic the schizophrenia phenotype. In this experiment, we assessed whether neonatal exposure to MK-801 (postnatal days 5-14) could induce sensitization to both hyperactivity and PPI deficit caused by later-life acute MK-801 treatment during adolescence or adulthood. Our results showed that the hyperactivity induced by an acute MK-801 challenge was enhanced in male and female rats after neonatal MK-801 treatment. Notably, in the PPI test, adult female rats neonatally exposed to MK-801 exhibited a significantly greater reduction in PPI in response to acute MK-801 administration, whereas male rats receiving neonatal MK-801 treatment expressed attenuated PPI disruption in adulthood. Our data indicate that a combination of neonatal and later-life NMDA receptor blockades could induce sensitization in the locomotor activity of both sexes in adolescence and adulthood. In addition, a sex difference was observed in the effects of this treatment regime on PPI.

Visuospatial working memory is impaired in an animal model of schizophrenia induced by acute MK-801: An effect of pretraining

Deficient working memory was proposed as an endophenotype of schizophrenia. Such deficits are also commonly found in animal models of schizophrenia-like behavior of various origins. An allothetic place avoidance alternation task was proposed as a behavioral test of visuospatial working memory. This study tested the hypothesis that working memory in this test would be impaired by acute pre-test treatment with MK-801 (dizocilpine) in an animal model possessing high phenomenological and predictive validity. Furthermore, the study sought to determine the effect of pretraining to the task prior to treatment on the subsequent learning in the animal model. The results show that both doses of MK-801 (0.12mg/kg and 0.15mg/kg) significantly impaired working memory in the alternation paradigm, and both doses also increased locomotor activity. Notably, in previously pretrained animals, the significant effect of MK-801 on working memory was absent, despite persistent hyperlocomotion. These results showed that a deficit in working memory was detectable in this animal model of schizophrenia-like behavior, but its occurrence depended on the previous experience of animals with familiarization in the task.

Two learning tasks provide evidence for disrupted behavioural flexibility in an animal model of schizophrenia-like behaviour induced by acute MK-801: A dose–response study

Schizophrenia is a chronic and devastating illness. Exact causes of the disease remain elusive; however, neurodevelopmental changes in the brain glutamate system are recognized to play an important role. Several animal models of the disease are induced by a systemic blockade of N-methyl-d-aspartate (NMDA) receptors. This study examined the animal model of schizophrenia-like behaviours induced by acute treatment with MK-801, a non-competitive NMDA-receptor antagonist. Behavioural flexibility is an ability to adapt to the changes in environment, and schizophrenia is often accompanied by its decrease. The study tested the effect of MK-801 on behavioural flexibility in an active place avoidance task and the Morris water maze (MWM). Flexibility was tested under reversal conditions, i.e., after changing the location of the target. Each spatial task addressed different functions; continuous coordinate-frame segregation was present in the active place avoidance and precise place representation in the MWM. Results showed that reversal was altered in both tasks by MK-801 at doses of 0.10–0.15mgkg−1. Some impairment was observed in the active place avoidance task at 0.08mgkg−1. Swimming towards a visible platform was impaired only by the highest dose (0.15mgkg−1). The results demonstrate that a significant impairment of behavioural flexibility accompanies this acute animal model of schizophrenia-like behaviours, and that active place avoidance had higher sensitivity for such deficits than the MWM. This suggests the usefulness of the reversal paradigm in both tasks for examining novel drugs with antipsychotic and procognitive actions.

Behavioural consequences of IVC cages on male and female C57BL/6J mice

Recent developments in the technology to breed and house laboratory rodents for medical research has produced individually ventilated cage (IVC) systems. These IVC systems produce a cage environment significantly different to conventional cages. As it is not known in detail whether housing mice in IVCs impacts on their baseline and drug-induced behaviours compared to mice of conventional filter-top cages a comprehensive multi-tiered phenotyping strategy was used to test the behavioural consequences of IVC housing in male and female C57BL/6JArc mice. IVC had anxiety-like effects in the elevated plus maze, which were more pronounced in female mice whereas cognition and locomotion of all test mice were not modified by IVC housing. Mice raised in IVC cage systems were socially more active than mice of filter-top systems. Furthermore, males raised in IVC exhibited an increased sensitivity to the locomotor-stimulating effects of acute MK-801 treatment compared to males in conventional cages. In summary, this is the first study revealing the longer-term effects of IVC housing on social behaviours and the locomotor response to an acute MK-801 challenge. In conclusion, researchers upgrading their holding facilities to IVC housing may encounter a shift in experimental outcomes (e.g. post pharmacological challenges) and the behavioural phenotype of test mice. Furthermore, differences between the housing conditions of breeding facilities and test facilities must carefully be considered. Finally, researchers should clarify in detail the type of housing test animals have been exposed to when publishing experimental animal research data.