Interaction between alpha- and beta-adrenergic receptor agonists modulating the slow Ca(2+)-activated K+ current IAHP in hippocampal neurons

Eur J Neurosci. 1996 Oct;8(10):2098-110. doi: 10.1111/j.1460-9568.1996.tb00731.x.


Noradrenaline inhibits the Ca(2+)-activated K+ current IAHP, which underlies the slow afterhyperpolarization and spike frequency adaptation in hippocampal and neocortical neurons. The resulting increase in excitability probably contributes to the state control of the forebrain during arousal and attention. The modulation of IAHP by noradrenaline has previously been shown to be mediated by beta 1 receptors, cyclic AMP and protein kinase A, but not by alpha receptors. We have now tested the possibility that alpha receptors also contribute to IAHP modulation through interaction with beta receptors, by the use of whole-cell recordings in CA1 pyramidal cells of rat hippocampal slices. The alpha-receptor agonist 6-fluoro-noradrenaline strongly potentiated the effect of isoproterenol on IAHP. The synergistic effect of 6-fluoro-noradrenaline and isoproterenol was blocked by the beta-receptor antagonist timolol, but the receptor type mediating the effect of 6-fluoro-noradrenaline could not be unequivocally identified by using alpha-receptor antagonists. The effect of high concentrations of noradrenaline on IAHP was only partly blocked by the beta-receptor antagonist timolol, and was further reduced by blocking alpha receptors, again suggesting a contribution from alpha receptors. In contrast, the effect of low concentrations of noradrenaline seemed to be potentiated by the alpha-receptor antagonist phentolamine in 57% of the cells, suggesting concentration-dependent antagonistic interaction between alpha and beta receptors. Further tests indicated that the cross-talk between 6-fluoro-noradrenaline and isoproterenol occurs upstream from cyclic AMP production, and that protein kinase A serves as a final common path for the modulation of IAHP by noradrenaline, and by the combination of 6-fluoro-noradrenaline and isoproterenol.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic alpha-Agonists / pharmacology*
  • Adrenergic beta-Agonists / pharmacology*
  • Animals
  • Calcium / pharmacology*
  • Colforsin / pharmacology
  • Cyclic AMP / analogs & derivatives
  • Cyclic AMP / pharmacology
  • Cyclic AMP-Dependent Protein Kinases / antagonists & inhibitors
  • Drug Interactions
  • In Vitro Techniques
  • Norepinephrine / pharmacology*
  • Potassium Channels / agonists*
  • Pyramidal Cells / drug effects*
  • Pyramidal Cells / metabolism
  • Rats
  • Rats, Wistar
  • Thionucleotides / pharmacology
  • Time Factors


  • Adrenergic alpha-Agonists
  • Adrenergic beta-Agonists
  • Potassium Channels
  • Thionucleotides
  • Colforsin
  • 8-((4-chlorophenyl)thio)cyclic-3',5'-AMP
  • Cyclic AMP
  • Cyclic AMP-Dependent Protein Kinases
  • Calcium
  • Norepinephrine