THE POTASSIUM CHANNEL BLOCKERS 4-AMINOPYRIDINE AND TETRAETHYLAMMONIUMINCREASE THE SPONTANEOUS BASAL RELEASE OF [H-3] 5-HYDROXYTRYPTAMINE IN RAT HIPPOCAMPAL SLICES

Previous investigations have demonstrated that compounds capable of bl ocking presynaptic potassium channels can stimulate neurotransmitter r elease at both peripheral and central synapses. This study examined th e in vitro effects of the ''classical'' potassium channel blockers 4-a minopyridine (4-AP) and tetraethylammonium (TEA) on the spontaneous ba sal release of [H-3]5-hydroxytryptamine ([H-3]5-HT) from rat hippocamp al slices using an automated superfusion apparatus. 4-AP and structura l analogs increased the spontaneous basal release of [H-3]5-HT in a co ncentration-related manner. The rank order of potencies from the estim ated EC50 values indicated that 3,4-diaminopyridine (0.88 mM) approxim ate to 4-AP (1.2 mM)> 2-AP (89 mM)> 3-AP (100 mM) > pyridine (256 mM). TEA stimulated [H-3]5-HT release with an estimated EC50 value of 63 m M and was less efficacious than the pyridine congeners. The enhancemen t release induced by 1 mM 4-AP was additive with 100 mM TEA and 5 mu M veratridine but not with 3,4-diaminopyridine or KCl (25 and 50 mM). T he release induced by 4-AP (0.3, 1 and 10 mM) and TEA (30, 100 and 300 mM) was significantly attenuated in a calcium-free buffer containing 1 mM ethylene glycolbis(b-aminoethyl ether N,N,N',N'-tetraacetic acid. Tetrodotoxin (1 mu M), a sodium channel blocker, was unable to block the response to 4-AP (1 mM) and TEA (100 mM). Notably, this concentrat ion of tetrodotoxin reduced the stimulation of [H-3]5-HT release produ ced by the sodium channel opener veratridine (5 mu M). Taken together, the results demonstrate that potassium channel blockade can enhance t he spontaneous basal release of [H-3]5-HT in rat hippocampal slices. T hese effects are at least partly dependent on extracellular calcium an d do not appear to be mediated by modulating sodium channel function.