The aim of this study was to show whether reduction or loss of cortical cholinergic activity results in any particular change in the expression of the proto-oncogenes c-fos and/or c-jun. To produce cortical cholinergic hypofunction, the monoclonal antibody, 192IgG, to the low-affinity nerve growth factor receptor p75NGFR coupled to a cytotoxin, saporin, was used as an efficient and selective immunotoxin for cholinergic neurons in rat basal forebrain. Brain sections of adult rats that had received an intracerebroventricular injection of 4 micrograms of the 192IgG-saporin were subjected to in situ hybridization using oligonucleotides to detect c-fos and c-jun mRNA. Autoradiographs obtained were evaluated by quantitative image analysis. Seven days following injection of the immunotoxin there was a dramatic loss in acetylcholinesterase staining in frontal, parietal, piriform, temporal, and occipital cortices, hippocampus, and olfactory bulb, but not in the striatum and cerebellum. In situ hybridization revealed a considerable increase in the level of c-fos mRNA in the lateral septum following the cholinergic lesion, whereas in the medial septum both c-fos and c-jun mRNA were elevated. Immunolesioning led to a distinct and specific increase in the level of c-jun but not c-fos mRNA in the parietal and occipital cortex that was restricted to cortical layer IV. These data suggest that reduced cortical cholinergic activity differentially regulates expression of c-fos/c-jun genes in distinct cortical regions of the rat brain.