1. ¹Department of Neuroscience, Norwegian University of Science and Technology (NTNU), Trondheim, Norway
2. ²Department of Neurology and Neurobiology Research Unit, Rigshospitalet, Copenhagen, Denmark
3. ³Carlsson Research AB, Biotech Center, Arvid Wallgrens Backe 20, Göteborg, Sweden
4. ⁴Arvid Carlsson Institute, Institute of Clinical Neuroscience, Göteborg University, Medicinaregatan 11, Göteborg, Sweden

Correspondence: Professor U Sonnewald, Department of Neuroscience, Faculty of Medicine, NTNU, Olav Kyrres gate 3, Trondheim N-7489, Norway. Tel: +47 73590492; Fax: +47 73598655; E-mail: Ursula.Sonnewald@ntnu.no

Received 19 May 2005; Revised 18 October 2005; Accepted 24 October 2005; Published online 14 December 2005.

Abstract

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 [1-¹³C]glucose and [1,2-¹³C]acetate. Extracts from frontal, retrosplenial, and cingulate cortices (CRFC) and temporal lobes were examined by ¹³C 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 [1,2-¹³C]acetate and thus astrocytes, were significantly decreased in CRFC as compared to controls. Labeling from [1-¹³C]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.