4‐Aminopyridine‐induced increase in basal and stimulation‐evoked [ 3 H]‐NA release in slices from rat hippocampus: Ca 2+ 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 [ 3 H]‐noradrenaline ([ 3 H]‐NA) release and the [ 3 H]‐NA release evoked by electrical stimulation, but not the release of [ 3 H]‐acetylcholine ([ 3 H]‐ACh), from slices of rat hippocampus. 2 Both the electrically evoked and the 4‐AP‐induced release were blocked by tetrodotoxin (TTX) (3 μ m ). The Ca 2+ ‐dependence of the 4‐AP‐induced release (EC 50 0.15 m m ) was, however, different from that of the electrically evoked [ 3 H]‐NA release (EC 50 0.76 m m ). 3 The 4‐AP‐induced release could be inhibited by CdCl 2 (10 μ m ) and ω‐conotoxin (30 n m ), but not by nifedipine (1 μ m ). 4 Transmitter release evoked by 100 μ m 4‐AP could be blocked by the α 2 ‐adrenoceptor agonist, UK 14,304 (0.1 μ m ) and by the A 1 ‐receptor agonist R ‐N 6 ‐phenylisopropyl adenosine ( R ‐PIA, 1 μ m ) and increased by the α 2 ‐adrenoceptor antagonist, yohimbine (1 μ m ), both in 0.25 and 1.3 m m Ca 2+ ‐containing medium. By contrast, the effect of α 2 ‐adrenoceptor agonists and antagonists on transmitter release evoked by electrical stimulation was markedly reduced in the presence of 4‐AP (100 μ 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 Ca 2+ . Furthermore, the fact that α 2 ‐receptors and adenosine A 1 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.