Cyclic AMP phosphodiesterases are localized in regions of the mouse brain associated with reinforcement, movement, and affect

Four cyclic AMP-specific, rolipram-inhibited phosphodiesterases (PDE4s) hav e been identified in mammals; all four are homologs of dunce, a gene requir ed for learning and memory in Drosophila. To determine the distribution of PDE4s in the mammalian brain, specific antibodies were generated against th e proteins encoded by each of three dunce homologs PDE4A, PDE4B, and PDE4D in the mouse. On Western blots, these antibodies recognized multiple protei n species in all brain regions studied. Immunohistochemical studies showed that both cell bodies and neuropil were well labeled in selected regions th roughout the brain. Immunoreactivity for PDE4A was found predominantly in t he anterior olfactory nucleus, subiculum, layer V pyramidal neurons from th e cerebral cortex, and corticospinal tracts. By contrast, anti-PDE4B-labele d neurons were observed in the inferior olive, the paraventricular and supr aoptic nuclei of the hypothalamus, and in the ventral striatum. Regions of neuropil containing high levels of PDE4B immunoreactivity included the cere bellar molecular layer, globus pallidus, nucleus accumbens, and substantia nigra. Anti-PDE4D antibody distinctly labeled cerebellar Purkinje cells as well as neurons in the medial habenula and thalamic nuclei. Fibers in the f asciculus retroflexus, interpeduncular nuclei, and periaqueductal gray were also stained with this antibody. These findings indicate that the distribu tion of PDE4s in the brain is remarkably segregated, and suggest that each of these enzymes has a unique functional role. Furthermore, the data suppor t the notion that rolipram, the PDE4-specific inhibitor that acts as an ant idepressant in humans, may mediate its behavioral effects through PDE4B, wh ich is highly localized to neural pathways known to underlie reward and aff ect in mammals. J. Comp. Neurol. 407:287-301, 1999. (C) 1999 Wiley-Liss, In c.