GENE-EXPRESSION STUDIES OF MESSENGER-RNAS ENCODING THE NMDA RECEPTOR SUBUNITS NMDAR1, NMDAR2A, NMDAR2B, NMDAR2C, AND NMDAR2D FOLLOWING LONG-TERM TREATMENT WITH CIS-FLUPENTIXOL AND TRANS-FLUPENTIXOL AS A MODEL FOR UNDERSTANDING THE MODE OF ACTION OF SCHIZOPHRENIA DRUG-TREATMENT

It has been hypothesized that glutamate receptor function is important in both the aetiology and treatment of schizophrenia. In order to und erstand how specific glutamate receptor genes are involved in the trea tment of schizophrenia we have used a multiprobe oligonucleotide solut ion hybridization (MOSH) technique to examine the regulation of gene e xpression of the NMDAR1, 2A, 2B, 2C, 2D receptor subunits in the left rat brain following treatment with the optical isomers of flupenthixol . cis-and trans-flupenthixol are both present in the commonly used ora l and depot treatments for schizophrenia and a controlled trial showed that cis-flupenthxiol had a significantly superior ability to amelior ate the positive symptoms of schizophrenia compared to its trans-isome r. At a dose of 0.2 mg/kg/day over a period of 1, 2, 4, 8, 12 and 24 w eeks, we found that both isomers down regulated the expression of NMDA R1 mRNA in most regions of the brain. NMDAR2A, 2B and 2C receptor subu nits showed a significantly decreased expression from 12 to 24 weeks b ut after 2 weeks NMDAR2B, 2C, 2D expression was increased in several b rain regions. The NMDAR1 receptor subunit immunoreactivity in the righ t brain following 3 and 24 weeks of drug treatment was also examined b y Western blotting. Both trans-and cis-flupenthixol significantly decr eased the NR1 immunoreactivity in the right cerebellum after 24 Reeks of treatment. These results suggest that NMDA receptor subunits may ha ve a role in the action of antipsychotic drugs. If we assume that the NMDA receptor expression changes reflect a beneficial and significant mechanism in the treatment of schizophrenia, it could be argued that N MDA receptor changes are more related to the negative or non-specific symptoms of schizophrenia. (C) 1998 Elsevier Science B.V.