The aim of the study was to determine whether the haloperidol-produced induction of the c-fos gene in the mouse striatum is the cause of the increased expression of the striatal proenkephalin (PENK) gene after repeated haloperidol administration. Mice were treated with haloperidol (1 mg/kg, i.p., once daily), MK-801 (1 mg/kg, i.p., twice daily), or with both those drugs for 9 days. Pretreatment with MK-801 prevented the haloperidol-produced induction of the striatal c-fos mRNA. In animals injected with haloperidol for 9 days, levels of the striatal PENK mRNA were increased by 100%. Coadministration of MK-801 did not reduce that increase. These results suggest that Fos is not necessary for activation of the PENK gene expression, produced by chronic haloperidol application, in the striatum.