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OtherNEUROPHARMACOLOGY

Age-Related Deficits in the Cerebellar BetaAdrenergic Signal Transduction Cascade in Fischer 344 Rats

Thomas J. Gould and Paula C. Bickford
Journal of Pharmacology and Experimental Therapeutics May 1997, 281 (2) 965-971;
Thomas J. Gould
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Paula C. Bickford
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Abstract

Localization of age-related deficits in the cerebellarbeta adrenergic signal transduction cascade were investigated electrophysiologically using forskolin (FORSK) and adenosine-3′,5′-cyclic monophosphothioate Sp-isomer (Sp-cAMPS) appliedvia pressure ejection from extracellular multibarreled glass electrodes to activate the transduction cascade. In young rats, 100 μM FORSK activated AC, and 100 μM Sp-cAMPS activated protein kinase A; thus, both increased GABAergic inhibition of Purkinje cell firing. In aged rats, however, 100 μM FORSK was unable to increase GABAergic inhibition of Purkinje cell firing. In addition, 1 mM 7β-decacetyl-7β-(γ-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.

Footnotes

  • Send reprint requests to: Dr. Paula C. Bickford, Department of Pharmacology, C-236, University of Colorado Health Sciences Center, 4200 East Ninth Avenue, Denver, CO 80262. E-mail:Paula.Bickford{at}UCHSC.EDU

  • ↵1 This work was supported by United States Public Health Service Grants AG04418 (P.C.B.) and AG05686 (T.J.G.) and the Department of Veterans Affairs; Medical Research Service (P.C.B.).

  • ↵2 Dr. Ronald Freund, personal communication.

  • Abbreviations:
    NE
    norepinephrine
    GABA
    γ-aminobutyric acid
    AC
    adenylyl cyclase
    cAMP
    cyclic adenosine-3′,5′-monophosphate
    ISO
    isoproterenol
    FORSK
    forskolin
    PDE
    phosphodiesterase
    PKA
    protein kinase A
    Sp-cAMPS
    adenosine-3′,5′-cyclic monophosphothioate sp-isomer
    DIDEOXY
    1,9-dideoxy-forskolin
    7β-FORSK
    7β-decacetyl-7β-(γ-N-methylpiperazino)butyryl-forskolin
    DMSO
    dimethylsulfoxide
    F344
    Fischer 344
    • Received June 10, 1996.
    • Accepted January 23, 1997.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 281, Issue 2
1 May 1997
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OtherNEUROPHARMACOLOGY

Age-Related Deficits in the Cerebellar BetaAdrenergic Signal Transduction Cascade in Fischer 344 Rats

Thomas J. Gould and Paula C. Bickford
Journal of Pharmacology and Experimental Therapeutics May 1, 1997, 281 (2) 965-971;

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OtherNEUROPHARMACOLOGY

Age-Related Deficits in the Cerebellar BetaAdrenergic Signal Transduction Cascade in Fischer 344 Rats

Thomas J. Gould and Paula C. Bickford
Journal of Pharmacology and Experimental Therapeutics May 1, 1997, 281 (2) 965-971;
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