Sammendrag
Traditionally most animal models of schizophrenia have focused primarily on dysfunction in the dopamine system, but more recent studies suggest that hypoactivity of NMDA (N-methyl-d-aspartate) receptors play a significant role in development and persistence of schizophrenia. In humans noncompetitive blockade of NMDA receptors by antagonists such as MK-801 and PCP emulate both the negative and positive symptoms of schizophrenia. The present study aimed to develop a rodent model of chronic schizophrenia by repetitive administration of NMDA receptor antagonists. Rats were given daily doses of MK-801 (0.5 mg/kg) or saline over a period of 6 days. On day 6, the rats received MK-801 together with [1-13C]glucose (543g/kg) plus [1,2-13C]acetate (504g/kg)15 min before decapitation. Analyses of extracts from the frontal cortex (consisting of cingulate cortex, retrosplenial cortex and parts of the prefrontal cortex) and temporal lobe were performed using 13C and 1H magnetic resonance spectroscopy. Animals receiving 0.5 mg/kg MK-801 showed characteristic behavioral changes, which lasted at least an hour. Repeated injections did not have any effect on duration or severity of behavioral changes in the experimental group. In the frontal cortex, administration of MK-801 led to an increased amount of glutamate, but the amount of 13C in glutamate and glutamine was reduced. These results demonstrate that glutamate metabolism and turn-over are both disturbed. These findings can explain the reduced amounts of glutamate detected in first episode schizophrenic patients with MR spectroscopy. This model appears well suited to study the cascade of events taking place in the development from first episode to chronic schizophrenia.
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