ALPHA(2)-ADRENOCEPTOR-MEDIATED INHIBITION OF ELECTRICALLY-EVOKED [H-3] NORADRENALINE RELEASE FROM CHICK SYMPATHETIC NEURONS - ROLE OF CYCLIC-AMP

This study explores the role of cyclic AMP in electrically evoked [H-3 ]noradrenaline release and in the alpha(2)-adrenergic modulation of th is release in chick sympathetic neurons. Along with an increase in sti mulation-evoked tritium overflow, applications of forskolin enhanced t he formation of intracellular cyclic AMP. Both effects of forskolin we re potentiated by the phosphodiesterase inhibitor 3-isobutyl-1-methylx anthine. The forskolin-induced increase in overflow was abolished by t he Rp-diastereomer of cyclic AMP-thioate, an antagonist at cyclic AMP- dependent protein kinases, and 1,9-dideoxyforskolin, an inactive analo gue at adenylyl cyclase, had no effect on the evoked overflow. A 24-h pretreatment with either cholera toxin or forskolin reduced the subseq uent forskolin-induced accumulation of cyclic AMP and inhibited the st imulation-evoked release. Basal cyclic AMP production, however, remain ed unaltered after forskolin treatment and was enhanced after 24 h of cholera toxin exposure. The alpha(2)-adrenergic agonist bromoxidine di d not affect the formation of cyclic AMP stimulated by forskolin but r educed electrically evoked release. However, effects of bromoxidine on H-3 overflow were attenuated by forskolin as well as by 8-bromo-cycli c AMP. Effects of bromoxidine on [H-3]noradrenaline release were paral leled by an inhibition of voltage-activated Ca2+ currents, primarily t hrough a delayed time course of current activation. This effect was ab olished when either forskolin or 8-bromo-cyclic AMP was included in th e pipette solution. Both substances, however, failed to affect Ca2+ cu rrents in the absence of bromoxidine. These results suggest that the s ignaling cascade of the alpha(2)-adrenergic inhibition of noradrenalin e release involves voltage-activated Ca2+ channels but not cyclic AMP. Elevated levels of cyclic AMP, however, antagonize this alpha(2)-adre nergic reduction, apparently through a disinhibition of Ca2+ channels.