DIFFERENTIAL CHANGES IN GLUTAMATE-RECEPTOR SUBUNIT MESSENGER-RNAS IN RAT-BRAIN AFTER HALOPERIDOL TREATMENT

Glutamate receptors are implicated in several neuropsychiatric disorders and in the actions of neuroleptic drugs used to treat them. To help clarify how these drugs impinge upon the glutamatergic system, we have studied the effects of 2 weeks' haloperidol (2 mg kg(-1) d(-1)) upon the distribution and abundance of glutamate receptor mRNAs in rat brain. The mRNAs detected were those encoding the glutamate-binding protein (GBP), the N-methyl D-aspartate (NMDA) receptor (NR1 subunit) and the flip and flop isoforms of alpha-amino-3-hydroxy-5-methyl-4-isoxazolpropionate (AMPA)-preferring non-NMDA receptors gluR1 and gluR2. The mRNAs were studied using in situ hybridization histochemistry in dorsolateral striatum, nucleus accumbens, frontal cortex and hippocampus. Haloperidol led to an increase in GBP mRNA in striatum and frontal cortex but not in hippocampus. AMPA receptor mRNAs showed gene- and isoform-specific alterations in treated animals, with a significant increase in the proportion of gluR2 flip compared to gluR2 flop. The gluR1 flop:gluR2 flop ratio also increased. No differences were observed for NR1 mRNA in any area. Thus, subchronic administration of haloperidol has a molecularly and spatially specific effect upon expression of glutamate receptor-related transcripts. The data have several implications. Firstly, the enhanced expression of GBP mRNA may contribute to the alterations in other glutamatergic parameters observed after neuroleptics. Secondly, the pattern of changes for the NMDA and AMPA receptor mRNAs suggests that the alterations in density of these receptors and their mRNAs reported in schizophrenia are not an artefact of neuroleptic treatment. Finally, the specific increase in flip:flop mRNA ratio for gluR2, together with the increased proportion of gluR1 flop:gluR2 flop mRNA, is likely to affect the properties of the encoded AMPA receptors. Such changes may be relevant to the desired or undesired effects of these drugs.