Noradrenergic lesions differentially alter the expression of two subtypes of low Km cAMP-sensitive phosphodiesterase type 4 (PDE4A and PDE4B) in rat brain

This study examined the effects of selective, central noradrenergic dennerv ation with 6-hydroxydopamine (6-OHDA) on the expression of type 4 phosphodi esterases (PDE). Twenty-one days following i.c.v. injection of 6-OHDA (200 mu g) hypothalamus, neostriatum, and cerebellum were dissected. Infusion of 6-OHDA reduced norepinephrine (NE) content in all the brain areas examined (to 17%. 76% and 16% of sham-operated controls in hypothalamus, striatum, and cerebellum, respectively). 6-OHDA injections also reduced dopamine leve ls in hypothalamus (53%) and neostriatum (68%). Administration of desiprami ne (20 mg/kg, i.p.) 30 min prior to 6-OHDA injection protected neostriatal and cerebellar noradrenergic neurons NE levels (110-122% of the control lev els). Desipramine partially attenuated the 6-OHDA-mediated decrease in NE c ontent of hypothalamus, bur had little or no effect on either striatal or h ypothalamic dopamine (DA) levels. Western blot analysis using a PDE4A-selec tive antibody revealed three major bands (109 kDa PDE4A5, 102 kDa PDE4AX an d 76 kDa PDE4A1) in hypothalamus and striatum. Infusion of 6-OHDA decreased the expression of PDE4A5 and PDE4AX but not of PDE4A1 in hypothalamus, as determined by quantitative Western blotting. Pretreatment of rats with desi pramine attenuated the 6-OHDA-induced down-regulation of PDE4A5 and PDE4AX bands in hypothalamus. The PDE4B selective antibody K118 labels 5 major ban ds in all the brain regions studied. One hundred kDa PDE4B3, 86 kDa PDE4B2, and a 78 kDa PDE4B band was identified using recombinant proteins. Treatme nt of rats with 6-OHDA resulted in a 52% decrease in the PDE4B3 and 58% dec rease in 78 kDa PDE4B variant in hypothalamus; administration of desipramin e attenuated the 6-OHDA-induced down-regulation of both PBE4B variants. Nei ther 6-OHDA nor desipramine altered striatal PDE4A or PDE4B isozymes. In co ntrast, cerebellar PDE4B3 variant is up-regulated by 6-OHDA treatment and w ere partially normalized to control values by desipramine pretreatment. The se data demonstrate that PDE4 subtypes are differentially regulated by pres ynaptic noradrenergic activity and may play an important roll: in the maint aining homeostasis of noradrenergic signal transduction in rat brain. (C) 2 000 Elsevier Science B.V. All rights reserved.