Age-related deficits in the cerebellar beta adrenergic signal transduction cascade in Fischer 344 rats.
Localization of age-related deficits in the cerebellar beta adrenergic signal transduction cascade were investigated electrophysiologically using forskolin (FORSK) and adenosine-3',5'-cyclic monophosphothioate Sp-isomer (Sp-cAMPS) applied via pressure ejection from extracellular multibarreled glass electrodes to activate the transduction cascade. In young rats, 100 microM FORSK activated AC, and 100 microM Sp-cAMPS activated protein kinase A; thus, both increased GABAergic inhibition of Purkinje cell firing. In aged rats, however, 100 microM FORSK was unable to increase GABAergic inhibition of Purkinje cell firing. In addition, 1 mM 7 beta-decacetyl-7 beta-(gamma-N-methylpiperazino)butyryl-forskolin, an analog of FORSK, was also unable to increase GABAergic inhibition in aged rats. In contrast, Sp-cAMPS was able to increase GABAergic inhibition in aged rats, but higher doses were required than in young rats, Isoproterenol (ISO), a beta adrenergic agonist, was ineffective in increasing GABAergic inhibition of Purkinje firing in aged rats when tested alone, but ISO was effective in increasing Purkinje cell inhibition when ISO was tested with Sp-cAMPS. The results of this experiment indicate that one age-related deficit in the cerebellar beta adrenergic system occurs at the level of protein kinase A activation.
Gould
T J
TJ
Department of Pharmacology, University of Colorado Health Sciences Center Denver, USA.
Bickford
P C
PC
D000375:Aging / Q000378:metabolism*; D000818:Animals; D002531:Cerebellum / Q000187:drug effects / Q000378:metabolism*; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000494:pharmacology; D008297:Male; D051381:Rats; D011916:Rats, Inbred F344; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D011943:Receptors, Adrenergic, beta; D005576:Colforsin; D005680:gamma-Aminobutyric Acid; D000242:Cyclic AMP