Glial-neuronal interactions are impaired in the schizophrenia model of repeated MK801 exposure.

Schizophrenia-mimicking compounds such as phencyclidine (PCP) and MK801 are antagonists at the N-methyl-D-aspartate (NMDA) receptor and produce the whole spectrum of positive, negative, and cognitive symptoms. This is one of the most important pillars of the hypoglutamatergic hypothesis of schizophrenia. Since the synthesis of glutamate and GABA in neurons is closely connected to astrocyte metabolism, the study of astrocytic function is essential in this context. Dizocilpine-maleate (MK801) (0.5 mg/kg) was injected into rats every day for 6 days. The last dose was given together with [1-(13)C]glucose and [1,2-(13)C]acetate. Extracts from frontal, retrosplenial, and cingulate cortices (CRFC) and temporal lobes were examined by (13)C nuclear magnetic resonance spectroscopy, high pressure liquid chromatography, and light microscopy. In CRFC, significant increases in the levels of glutamate, glutathione, and taurine were seen, whereas amounts and turnover of noradrenaline, dopamine, and serotonin were unchanged. Glutamate and glutamine, derived from [1,2-(13)C]acetate and thus astrocytes, were significantly decreased in CRFC as compared to controls. Labeling from [1-(13)C]glucose and thus mostly neuronal metabolism was affected in the same brain region with decreased labeling of glutamate and GABA. The present model mimics the increased glutamate/glutamine activity found in drug-naive patients with first episode schizophrenia. Moreover, the decreased labeling indicates the transition to lower glutamatergic function seen in chronic schizophrenia patients. The disturbance in astrocytic function and the glutamine-glutamate-GABA cycle are of significant importance and might add to the malfunction of the cortico-striato-thalamo-cortical loop caused by NDMA receptor blockade.

Differential effects of classical neuroleptics and a newer generation antipsychotics on the MK-801 induced behavioural primitivization in mouse.

Cognitive dysfunction plays an important role in mental disorders like schizophrenia and may involve inadequate glutamatergic signalling in different regions of the brain, mediated by e.g. glutamatergic N-methyl-D-aspartate (NMDA) receptors. In rodents, NMDA receptor antagonists often increase motor activity; in addition they induce a more primitive and undifferentiated behavioural pattern, which we believe may correspond to some of the cognitive defects seen in schizophrenia. In the present study, the movement pattern of mice treated with the uncompetitive NMDA receptor antagonist MK-801 in conjunction with six antipsychotic agents, some with reported clinical effects on cognition, was characterised and quantified. The classical neuroleptic drugs chlorpromazine and trifluoperazine, the atypical antipsychotic agents ziprasidone and olanzapine, the gamma-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)-receptor potentiator CX516 and the serotonin (5-HT)2A-antagonist M100907 were tested. In accordance with previous observations, MK-801 was found to induce a primitive and monotonous behavioural pattern dominated by forward locomotion; spatial movements, the number of switches between the states moving and stationary, and rearing frequency were reduced. All test substances counteracted MK-801-induced hyperactivity, but differed in their ability to improve behavioural quality. Chlorpromazine and trifluoperazine were unable to restore behavioural diversity while ziprasidone, olanzapine, CX516 and M100907 restored it to varying degrees. A striking similarity in movement pattern was seen between the hypoglutamatergic mice treated with the AMPA-receptor agonist CX516, and those receiving the 5HT2A-antagonist M100907.

The dopaminergic stabilizers (-)-OSU6162 and ACR16 reverse (+)-MK-801-induced social withdrawal in rats.

Schizophrenia is manifested by positive and negative symptoms, as well as cognitive deficits. Most existing antipsychotic agents have poor effects on the negative symptoms of schizophrenia, thus emphasizing the necessity for developing new antipsychotic treatments. Dopaminergic stabilizers constitute one of the latest novelties in the quest for new antipsychotic drugs. Social withdrawal in rats, in response to treatment with NMDA-receptor antagonists such as (+)-MK-801, may be used to model negative symptoms. In this study we aimed to evaluate the dopaminergic stabilizers (-)-OSU6162 and ACR16, compared to haloperidol and clozapine, in a rat model for schizophrenia, focusing on (+)-MK-801 induced social withdrawal. Social behaviour and motor activity were assessed using a videotracking system, allowing automated analysis of the behaviour. Both (-)-OSU6162 and ACR16 were capable of restoring social behaviour, measured as proximity, to control level. These results indicate that these drugs may be effective in the treatments of negative symptoms.

The dopaminergic stabiliser ACR16 counteracts the behavioural primitivization induced by the NMDA receptor antagonist MK-801 in mice: implications for cognition.

The Carlsson research group has developed a series of compounds capable of stabilising the dopamine system without inducing the deleterious hypodopaminergia that encumbers the currently used antipsychotic drugs. In the present study one of these dopaminergic stabilisers, ACR16, was tested in a mouse model for cognitive deficits of schizophrenia and autism. Since we believe that hypoglutamatergia is a key element in both schizophrenia and autism we used mice rendered hypoglutamatergic by treatment with the N-methyl-D-aspartate (NMDA) antagonist MK-801. MK-801 causes both hyperactivity and a behavioural primitivization. ACR16 attenuated the MK-801-induced hyperactivity and, in addition, caused a marked improvement of behavioural quality with a movement pattern approaching that of control animals. Since we believe that the impoverishment of the behavioural repertoire caused by MK-801 may correspond to the cognitive deficits seen in schizophrenia and autism, these results suggest that ACR16 may improve cognitive status in these disorders.