We have characterized the effects of chronic clozapine and haloperidol treatments on the expression of fos (c-fos, fosB, fra-2) and jun (c-jun, junB, junD) family genes in the rat forebrain. The effects of chronic (17d) clozapine and haloperidol on mRNA expression were determined two hours, 24 hours, and six days after the last drug injection, and the DNA-binding activity of the activator protein-1 (AP-1) complex was studied after washout periods of 24 hours and six days. Chronic clozapine treatment with a 6 d washout period induced the expression of several fos and jun family genes in cortical regions, including the prefrontal cortex (PFC), and in the caudate putamen and nucleus accumbens. Moreover, the DNA-binding activity of the AP-1 complex was greatly increased in the anterior cingulate cortex-PFC in mobility shift assays already after 24 h, and remained increased after a 6d washout period. Chronic administration of haloperidol upregulated fos and jun family mRNA expression that was detectable 24 h and 6 d after cessation of the treatment mainly in the cortex. However, the DNA-binding activity of the AP-1 complex was not altered in the anterior cingulate cortex-PFC by chronic haloperidol administration at any of the time points studied. Thus, chronic treatments with clozapine and haloperidol induce a long-lasting enhancement of fos and jun family transcription factors that continues for several days after the cessation of the treatments in the cortex. These lasting effects might represent events that are potentially involved in the mechanisms of antipsychotic drug action. © 2002 American College of Neuropsychopharmacology. Published by Elsevier Science Inc.