Changes in brain cyclic AMP (cAMP) have been suggested to underlie the clinical action of antidepressant treatments. Also, a regionally-selective regulation of cAMP-specific phosphodiesterases (PDEs) has been demonstrated for some antidepressants. To further investigate the effects of antidepressant treatments on PDEs, we examined the expression of different cAMP-specific PDEs in the brain of rats treated (1 and 14 days) with fluoxetine 3 mg/kg day. The mRNAs coding for PDE4A, PDE4B, PDE4D, and the five known PDE4D splice variants were analyzed by in situ hybridization on 45 brain structures of acute and chronic fluoxetine-treated rats. We also examined the binding sites for the putative antidepressant drug [(3)H]rolipram, a PDE4-selective inhibitor. In some brain areas single fluoxetine administration increased the density of the mRNA of all PDE4 isozymes, except PDE4D and PDE4D5. Chronic fluoxetine treatment increased PDE4A mRNA levels and decreased those for PDE4B, PDE4D and PDE4D1 mRNAs in some brain regions. The study was complemented with the analysis of the expression of the transcripts of BDNF. Chronic fluoxetine treatment down-regulated the expression of BDNF. These results show that the expression of PDE4 isozymes is modulated by a clinically relevant fluoxetine dose. The significance of these changes in PDE4 expression to the antidepressant effect of fluoxetine is discussed.