ELSEVIER Neuroscience Letters 177 (1994) 3943 HEUROSClENCE lETTERS Lack of effect of antipsychotic and antidepressant drugs on glutamate receptor mRNA levels in rat brains Rossana G. Oretti, Gillian Spurlock, Paul R. Buckland*, Peter McGuffin Department of Psychological Medicine, University of Wales College of Medicine, Heath Park, Cardiff CF4 4XN, UK Received 19 May 1994; Revised version received 12 June 1994; Accepted 22 June 1994 Abstract By employing multiprobe oligonucleotide solution hybridisation (MOSH) we have measured the levels of mRNA encoding the NMDA receptor subtypes (R1, R2A, R2B and R2C) and the non-NMDA glutamate receptor subtypes (GIuR1, 2, 3, and 4) within rat brain following, 1-32 days of antipsychotic or antidepressant drug administration. The results suggest that the drugs studied do not significantly alter rat glutamatergic system mRNA levels when compared to controls. Key words: Glutamate receptor gene expression; Messenger RNA measurement; Antipsychotic; Antidepressant; There are many different theories proposed to link the excitatory amino acid glutamate to schizophrenia [10]. Kim et al., on the basis of low levels of glutamate in the cerebrospinal fluid (CSF) of schizophrenic patients, pro- posed that glutamatergic hypofunction was of primary significance to the aetiology of schizophrenia [16]. Indi- rect evidence for a role of glutamate in schizophrenia has come from observations that phencyclidine (PCP) can mimic both the positive and negative symptoms of schiz- ophrenia and that these behavioural effects are medi- ated, at least in part, by the ability of PCP to block the NMDA receptor [12]. Other NMDA antagonists can also produce psychosis [3]. Deutsch et al., have postu- lated that if antagonistic action at this site is psychoto- genic then it is conceivable that schizophrenia may be related to dysfunction of glutamatergic transmission at least at the level of the NMDA receptor [5]. Various post-mortem findings confirm an abnormality in glutamatergic neurotransmission in schizophrenia al- though the effects of chronic antipsychotic treatment have not been thoroughly excluded. Radioligand binding studies have suggested either that there is a decrease [14,15] or an increase [4,25] in the number of both non- *Corresponding author. 0304-3940/94/$7.00 © 1994 Elsevier Science Ireland Ltd. All rights reserved SSDI 0304-3940(94)00489-W NMDA receptors and glutamate uptake sites in the left medial temporal lobes and frontal cortices, respectively, in schizophrenic brains at necroscopy. However, Kerwin et al., have shown that there is no change in ligand binding to NMDA receptors in the medial temporal lobes of post-mortem schizophrenic brains [15]. Using in-situ hybridisation techniques Harrison et al., have demonstrated a specific loss of mRNA encoding for the GluR1 receptor in hippocampal tissue from post- mortem schizophrenic brains [7]. The regional and lateral specificity of the changes in glutamatergic trans- mission parallel established neuropathological abnor- malities detected in schizophrenic brains and although chronic psychotropic treatment may be of aetiological significance no effects of antipsychotic drugs on gluta- mate systems have been shown to date. However, some antidepressant drugs have been reported to upregulate mRNA encoding for the GIuR1 receptor but in the rat brain [8]. Antipsychotic drugs form the mainstay of pharmacological treatment of schizophrenia. Although dopamine receptor blockade occurs rapidly there is a therapeutic latency of weeks to months which has led to the suggestion that the antipsychotic effect is related to the occurrence of longer-term processes possibly arising within other neurotransmitter systems [11]. Indeed, sev- eral studies have indicated the existence of a reciprocal