The distribution of NMDA receptor subunit (NR1, NR2B) and glia-bound glutamate transporter (GLT1) mRNAs was investigated in postmortem brains of Huntington's disease (HD) patients and controls by means of in situ hybridization using radiolabeled deoxyoligonucleotides. In the neostriatum of HD, NR1, NR2B and GLT1mRNA decreased in correlation to disease severity. GLT1mRNA was not as low as NR1/NR2BmRNA. Losses were more prominent in putamen than in the distinctly atrophied caudate. NR1/NR2BmRNA decreased corresponding to neuronal loss, GLT1mRNA due to reduced cellular expression. The number of GLT1mRNA expressing cells identified as astrocytes increased in the neostriatum (astrogliosis). In contrast to controls, most of these astrocytes contained glial fibrillary acidic protein. NR1/NR2B and GLT1mRNA expression was not homogeneously lower in the neostriatum; zones with stronger hybridization signals corresponded to the matrix compartment and consisted of a larger number of cells with high mRNA levels. Early in the disease, cellular NR1/ NR2BmRNA levels were higher in these zones than in controls. These findings indicate a loss of neurons with NMDA receptors in the neostriatum of HD. A concomitant proliferation of astrocytes with GLT1 transcripts may represent a compensatory mechanism protecting neostriatal neurons from glutamate excitotoxicity.