Interaction Between α and β-Adrenergic Receptor Agonists Modulating the Slow Ca2+-activated K+ Current - IAHP in Hippocampd Neurons

Noradrenaline inhibits the Ca²⁺-activated K⁺ current I_AHP, 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 I_AHP by noradrenaline has previously been shown to be mediated by β₁ receptors, cyclic AMP and protein kinase A, but not by α receptors. We have now tested the possibility that a receptors also contribute to I_AHP modulation through interaction with β receptors, by the use of whole-cell recordings in CA1 pyramidal cells of rat hippocampal slices. The α-receptor agonist 6-fluoro-noradrenaline strongly potentiated the effect of isoproterenol on I_AHP. The synergistic effect of 6-fluoro-noradrenaline and soproterenol was blocked by the β-receptor antagonist timolol, but the receptor type mediating the effect of 6-fluoro-noradrenaline could not be unequivocally identified by using α-receptor antagonists. The effect of high concentrations of noradrenaline on I_AHP was only partly blocked by the β-receptor antagonist timolol, and was further reduced by blocking α receptors, again suggesting a contribution from α receptors. In contrast, the effect of low concentrations of noradrenaline seemed to be potentiated by the α-receptor antagonist phentolamine in 57% of the cells, suggesting concentration dependent antagonistic interaction between α and β 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 I_AHP by noradrenaline, and by the combination of 6-fluoro-noradrenaline and isoproterenol.