Effects of noradrenergic lesions on the development of rolipram-sensitive, low-K(m), cyclic AMP specific phosphodiesterase in rat brain.
Rolipram-sensitive, low-K(m)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.
Zhang
K
K
Department of Pharmacology and Therapeutics, Louisiana State University School of Medicine, 1501 Kings Highway, Shreveport, LA 71130,USA. kz@mclean.harvard.edu
Farooqui
S M
SM
Jackson
K T
KT
O'Donnell
J M
JM
D000595:Amino Acid Sequence; D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000187:drug effects*; D001933:Brain Stem / Q000187:drug effects; D002531:Cerebellum / Q000187:drug effects; D002540:Cerebral Cortex / Q000187:drug effects; D000242:Cyclic AMP / Q000502:physiology*; D007700:Kinetics; D008969:Molecular Sequence Data; D016627:Oxidopamine / Q000633:toxicity; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011943:Receptors, Adrenergic, beta / Q000502:physiology*; D020889:Rolipram / Q000494:pharmacology*
D010726:Phosphodiesterase Inhibitors; D011943:Receptors, Adrenergic, beta; D016627:Oxidopamine; D000242:Cyclic AMP; D020889:Rolipram