A small surgical lesion of the parietal cortex induces an increase in gene expression varying from 172 to 980% in the entire homolateral cerebral cortex, as detected by quantitative in situ hybridization histochemistry. The mRNAs encoding the immediate early genes of the leucine zipper family (c-fos, c-jun, jun-B), the zinc finger family (zif268), the glucocorticoid receptor family (NGF1-B) and the interferon family (PC4) are increased within two hours after the lesion and return to normal levels at six hours. The mRNAs encoding neuropeptides cholecystokinin, neuropeptide Y, somatostatin and the synthetizing enzyme of the neurotransmitter gamma amino butyric acid, glutamic acid decarboxylase, are elevated within one day and return to normal levels after six days. The increase in CCK neuropeptide is followed by a decrease in the number of CCK binding sites 3 days after lesion, as measured by autoradiography using CCK-8 (sulphated) 1125-labelled with Bolton & Hunter reagent. An intraperitoneal injection of the NMDA receptor antagonist MK801, 30 min before surgery, prevented both the induction of immediate early gene expression and the increase of neuropeptide and glutamic acid decarboxylase mRNAs expression. This study demonstrates that a minimal cortical lesion induces extensive changes in gene expression and that some of the mechanism(s) leading to these changes involves the glutamate NMDA receptor.L. Van Brée is Research Fellow of the IRSIA Belgique. Supported by Belgian Grants from the FRSM (3.4574.90), FMRE (1992-95) and Ministére de la Politique Scientifique (PAI 1990-95) and Loterie Nationale (1991, 1993).