4-AMINOPYRIDINE-INDUCED INCREASE IN BASAL AND STIMULATION-EVOKED [H-3] NA RELEASE IN SLICES FROM RAT HIPPOCAMPUS - CA2+ SENSITIVITY AND PRESYNAPTIC CONTROL

1 We have examined the mechanisms by which the K+-channel blocker 4-aminopyridine (4-AP) can dose-dependently increase both basal [H-3]-noradrenaline ([H-3]-NA) release and the [H-3]-NA release evoked by electrical stimulation, but not the release of [H-3]-acetylcholine ([H-3]-ACH), from slices of rat hippocampus. 2 Both the electrically evoked and the 4-AP-induced release were blocked by tetrodotoxin (TTX) (3-mu-M). The Ca2+-dependence of the 4-AP-induced release (EC50 0.15 mM) was, however, different from that of the electrically evoked [H-3]-NA release (EC50 0.76 mM). 3 The 4-AP-induced release could be inhibited by CdCl2(10-mu-M) and omega-conotoxin (30 nM), but not by nifedipine (1-mu-M). 4 Transmitter release evoked by 100-mu-M 4-AP could be blocked by the alpha-2-adrenoceptor agonist, UK14,304 (0.1-mu-M) and by the A1-receptor agonist R-N6-phenylisopropyl adenosine (R-PIA, 1-mu-M) and increased by the alpha-2-adrenoceptor antagonist, yohimbine (1-mu-M), both in 0.25 and 1.3 mM Ca2+-containing medium. By contrast, the effect of alpha-2-adrenoceptor agonists and antagonists on transmitter release evoked by electrical stimulation was markedly reduced in the presence of 4-AP (100-mu-M). 5 The results suggest that 4-AP can depolarize some nerve endings in the central nervous system, leading to transmitter release that is dependent on nerve impulses and Ca2+. Furthermore, the fact that alpha-2-receptors and adenosine A1 receptor agonists can influence the release of NA evoked by 4-AP suggests that these drugs may have actions that are independent of blockade of aminopyridine-sensitive K+-channels.