Effects of noradrenergic lesions on the development of rolipram-sensitive, low- Km, cyclic AMP specific phosphodiesterase in rat brain

Abstract

Rolipram-sensitive, low- K m, cyclic AMP specific phosphodiesterase (PDE4) belongs to a superfamily of phosphodiesterases that hydrolyzes cyclic nucleotides. Ample evidence suggest that PDE4 is regulated by β-adrenergic receptors both in cultured cells and in adult rat brain. The present study investigated the effects of neonatal noradrenergic lesions on PDE4 in developing rat brain in comparison to that in the adult rats. Neonatal 6-hydroxydopamine treatment produced selective noradrenergic lesions (>80% loss of norepinephrine in cerebral cortex) without affecting dopaminergic systems. The lesions resulted in temporary reduction of PDE4 activity in cerebral cortex, cerebellum and brainstem. Lesions in the adult rats, on the other hand, did not alter PDE4 activity. Decreased PDE4 activity by neonatal noradrenergic lesions was due to a decrease in the V max of cAMP hydrolysis by PDE4, and not a change in the K m values. Immunoblot analysis showed that decreased PDE4 activity in cerebellum was associated with reduced expression of PDE4A5, PDE4A1, and several PDE4B variants. No change in the expression of any PDE4 subtype in cerebral cortex was detected with the antibodies used in this study. Neither the permanent loss of noradrenergic innervation in cerebral cortex, nor the permanent noradrenergic hyperinnervation in brainstem was accompanied by any permanent change in PDE4 activity. Decreasing PDE4 activity early after neonatal noradrenergic lesions might be important in maintaining constant concentrations of cAMP, which is critical for the cellular proliferation and differentiation that is active during this period.