Effects of Methiothepin and Lysergic Acid Diethylamide on Serotonin Release In Vitro and Serotonin Synthesis In Vivo: Possible Relation to Serotonin Autoreceptor Function

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Abstract
An invitro system characterizing the presynaptic serotonin [5-hydroxytryptamine ] (5-HT) autoreceptor which controls the release of 5-HT from rat brain slices is described. Using this system, methiothepin (1-10 .mu.M) 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 LSD and 5-methoxy-tryptamine (5-MT). The reversal of the methiothepin-enhanced 5-HT release from hypothalamic slices by LSD was not influenced by 0.3 .mu.M tetrodotoxin. The peripheral administration of LSD to rats reduces 5-HT synthesis and release by a mechanism thought to involve, in part, an autoreceptor-mediated reduction in impulse flow of 5-HT neurons. I.p. injection of methiothepin antagonized the LSD-induced reduction in hypothalamic 5-HT synthesis (5-hydroxytryptophan [5-HTP] accumulation) while exerting no influence by itself. 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-HTP accumulation by LSD showed regional differences in inhibition by methiothepin (hypothalamus > cortex > striatum) which paralleled the autoreceptor antagonist activity of methiothepin in vitro. Similar autoreceptor mechanisms control 5-HT release and synthesis in terminal 5-HT projection areas and that the reduction in 5-HT accumulation by LSD and the antagonism by methiothepin may represent a useful biochemical measure of 5-HT autoreceptor activity in vivo.