Microiontophoretic studies of the effects of cyclic nucleotides on excitability of neurones in the rat cerebral cortex

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Abstract
Responses of cerebral cortical neurons to the microiontophoretic application of acetylcholine, noradrenaline [norepinephrine], cyclic[c]AMP and cGMP were examined. The application of acetylcholine and cGMP to identified pyramidal tract neurons resulted in an increased frequency of firing in a large number of cells. Upon application of both substances to cells which could not be identified as pyramidal tract cells, a reduction in the frequency of spontaneous firing was sometimes observed. Careful current controls had no effect on the cells discussed here, indicating that the observed responses were not due to the iontophoretic currents. Also, the electro-osmotic ejection of cGMP (outward current) produced similar changes of cell firing to those which followed iontophoretic application (inward current). The microiontophoretic application of atropine resulted in a blockade of acetylcholine responses while leaving responses to cGMP unaffected. This suggests that cGMP was not acting indirectly by releasing acetylcholine from presynaptic endings. Ejection of cGMP from solutions containing Ca2+ produced responses comparable to those produced by cGMP alone. It was therefore unlikely that cGMP was causing excitation by chelating Ca2+. Applications of noradrenaline and cAMP produced a reduction in the spontaneous discharge rate of most neurons tested. Phosphodiesterase inhibitors such as ICI 63,197 [2-amino-6-methyl-5-oxo-4-n-propyl-4,5-dihydro-s-triazolo (1,5a) pyrimidine] caused a potentiation of the noradrenaline responses of pyramidal tract neurons. 5''-AMP produced a powerful depression of all cells to which it was applied. This action was blocked by aminophylline, suggesting the effect was mediated through an adenosine receptor. Responses to cAMP were usually not abolished, but were reduced by about 50% in amplitude. cAMP may mediate some neuronal effects of noradrenaline and cGMP may mediate some effects of acetylcholine. The 2 nucleotides may sometimes mediate opposite cellular responses to humoral stimuli.