ALPHA-2-ADRENOCEPTOR MEDIATED INHIBITION OF EXOCYTOTIC NORADRENALINE RELEASE IN THE ABSENCE OF EXTRACELLULAR CA2+

The effect of the alpha-2-adrenoceptor agonist clonidine on 3,4-diaminopyridine (3,4-DAP)-evoked [H-3]noradrenaline ([H-3]NA) release in rat hippocampus slices was studied in the presence or absence (+1 mM EGTA) of extracellular Ca2+. H-3 overflow (consisting mainly of unmetabolized [H-3]NA) was evoked by addition of 100-mu-M 3,4-DAP for 10 min to the medium, which always contained 1-mu-M desipramine. Ligands for L-type voltage-sensitive Ca2+ channels (VSCC) did not affect the evoked [H-3]NA release, whereas the preferential N-type VSCC antagonist omega-conotoxin was inhibitory, both in the presence and even more potently in the absence of Ca2+, suggesting an involvement of N-type VSCC in the mechanism of 3,4-DAP-evoked [H-3]NA release. In the absence of extracellular Ca2+ the initial Na+ influx, which has been previously proposed to liberate Ca2+ from intracellular stores for the exocytotic process, most probably occurs via N-type VSCC. Clonidine inhibited the 3,4-DAP-evoked [H-3]NA release in a concentration-dependent manner, both in the presence and even more potently in the absence of Ca"; its effects were antagonized by yohimbine. In the presence of extracellular Ca2+ the clonidine effect was not changed by addition of omega-conotoxin. Similar effects of clonidine were found in slices from the rabbit hippocampus. Since the availability of Ca2+ from intracellular stores seems to predominate in the present model, our results lend some support to the suggestion that alpha-2-adrenoceptor activation might affect intracellular mechanisms of Ca2+ homeostasis. On the other hand, however, the present data cannot completely exclude that alpha-2-autoreceptor activation leads to opening of presynaptic K+ channels, or that modulation of Ca2+ influx through VSCC is involved.