Effects of methiothepin and lysergic acid diethylamide on serotonin release in vitro and serotonin synthesis in vivo: possible relation to serotonin autoreceptor function.

An in vitro system characterizing the presynaptic serotonin (5-HT) autoreceptor which controls the release of 5-HT from rat brain slices is described. Using this system, methiothepin (1-10 microM) demonstrated 5-HT autoreceptor antagonist activity by enhancing 5-HT release, while several recognized postsynaptic 5-HT receptor antagonists were inactive: mianserin, cinanserin, cyproheptadine, methysergide. The activity of methiothepin was highest in hypothalamic slices and lowest in striatal slices and was inhibited by the autoreceptor agonists lysergic acid diethylamide (LSD) and 5-methoxytryptamine (5-MT). The reversal of the methiothepin-enhanced 5-HT release from hypothalamic slices by LSD was not influenced by 0.3 microM tetrodotoxin. The peripheral administration of LSD to rats has been shown to reduce 5-HT synthesis and release by a mechanism thought to involve, in part, an autoreceptor-mediated reduction in impulse flow of 5-HT neurons. In the present experiments, intraperitoneal injection of methiothepin antagonized the LSD-induced reduction in hypothalamic 5-HT synthesis (5-hydroxytryptophan accumulation) while exerting no influence by itself. Conversely, compounds which were not active as 5-HT autoreceptor antagonists in vitro (i.e., cyproheptadine, methysergide, cinanserin) did not influence the effect of LSD on 5-HT synthesis. Further, the reduction in 5-hydroxytryptophan (5-HTP) accumulation by LSD showed regional differences in inhibition by methiothepin (hypothalamus greater than cortex greater than striatum) which paralleled the autoreceptor antagonist activity of methiothepin in vitro.(ABSTRACT TRUNCATED AT 250 WORDS)