Attenuation of serotonin-induced suppression of [(3)H]acetylcholine release from rat cerebral cortex by minaprine: Possible involvement of the serotonin-2 receptor and K(+) channel.

5-Hydroxytryptamine (serotonin, 5-HT) and 5-HT(2) receptor agonist 4-bromo-2,5-dimethoxyphenylisopropylamine (DOB) inhibited K(+)-induced [(3)H]acetylcholine ([(3)H]ACh) release from slices and crude synaptosomes of rat cerebral cortex. Minaprine [3(2-morpholinoethylamino)-4-methyl-6-phenylpyridazine] and the 5-HT(2) receptor antagonists, ketanserin and methysergide, had no effect on [(3)H]ACh release alone. However, they attenuated the inhibition of [(3)H]ACh release by 5-HT and DOB. The attenuating effect of 5-HT was not mimicked by the 5-HT(1A) receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), neither was it prevented by the 5-HT(1A) and 5-HT(1B) mixed receptor antagonist, propranolol, or by the 5-HT(3) receptor antagonist, cocaine. Minaprine inhibited [(3)H]ketanserin binding more strongly than [(3)H]5-HT binding in the cerebral cortex. The inhibitory effect of minaprine on [(3)H]ketanserin binding was noncompetitive in Scatchard plot analysis. The inhibitory effect of 5-HT on [(3)H]ACh release was also suppressed by the voltage-dependent K(+) channel blockers, phencyclidine, tetraethylammonium (TEA) and 4-aminopyridine, but was not suppressed by the Ca(2+)-dependent K(+) channel blocker, apamin. These results suggest that minaprine suppresses the inhibitory effect of 5-HT on ACh release in the cerebral cortex by blocking the 5-HT(2) receptor and the voltage-dependent K(+) channel on the nerve endings of cholinergic neurons.