The effect of acute and chronic administration of dopamine receptor antagonists on the expression of mRNA encoding the cellular immediate-early gene c-fos was investigated in rat brain by in situ hybridization using 35S-labelled oligonucleotide probes. The selective dopamine D3 receptor antagonist GR103691 had no effect on the level of c-fos mRNA after acute or chronic treatment. Acute treatment with haloperidol increased the level of c-fos mRNA in the caudate-putamen, nucleus accumbens shell and core, olfactory tubercle and parietal cortex. After chronic treatment with haloperidol increases in the level of c-fos mRNA in the caudate-putamen and nucleus accumbens core were no longer observed. The increase in the level of c-fos mRNA in the nucleus accumbens shell was attenuated but still significantly elevated above the level measured in vehicle-treated animals. In the olfactory tubercle, parietal cortex, frontal cortex and cingulate cortex the level of c-fos mRNA was decreased after chronic haloperidol treatment. Acute sulpiride treatment reduced the level of c-fos mRNA in the olfactory tubercle, parietal cortex and cingulate cortex. After chronic treatment with sulpiride the level of c-fos mRNA was reduced in the dorsal caudate-putamen only. Acute clozapine treatment increased the level of c-fos mRNA in the nucleus accumbens shell and islands of Calleja. After chronic treatment with clozapine the level of c-fos mRNA remained elevated in the islands of Calleja but not in the nucleus accumbens shell. These results indicate that acute and chronic blockade of dopamine D3 receptors does not cause induction of c-fos transcription in limbic, striatal or cortical regions of rat brain. This study also demonstrated that acute blockade of dopamine receptors with haloperidol, sulpiride and clozapine induced different regionally specific patterns of c-fos expression which were altered after chronic blockade.