Further Studies on the Mode of Action of Psychotomimetic Drugs: Antagonism of the Excitatory Actions of 5‐hydroxytryptamine by Methylated Derivatives of Tryptamine

Abstract

1The actions of 5-methoxytryptamine (5-MeOT), N,N-dimethyltryptamine (DMT), 5-hydroxy-N,N-dimethyltryptamine (bufotenine, 5-HODMT) and 5-methoxy-N,Ndimethyltryptamine (5-MeODMT), and their interactions with 5-hydroxytryptamine (5-HT), acetylcholine, (-)-noradrenaline, and glutamate were studied by microiontophoresis on single neurones in the brain stem of rats anaesthetized with urethane or decerebrate cats. 2 Like D-lysergic acid diethylamide (LSD 25) the three psychotomimetic derivatives (DMT, 5-HODMT, 5-MeODMT) specifically antagonized 5-HT excitations of single neurones, but the non-psychotomimetic 5-MeOT had no antagonistic effects. 3 In contrast to LSD 25, the psychotomimetic tryptamines only rarely antagonized glutamate effects, indicating that the excitatory 5-HT receptors and the glutamate receptors on the same neurones may be closely related spatially, but are separate. 4 The methylated tryptamine derivatives were able to mimic the actions of 5-HT on neurones. The non-psychotomimetic 5-MeOT was most potent in this respect, while the other three derivatives which are psychotomimetic, were less active. 5 The 5-HT mimicking actions of 5-MeOT were the same in rats pretreated with p-chlorophenylalanine or reserpine as in untreated rats. It therefore seems that the 5-HT mimicking actions are unlikely to be due to release of 5-HT, but are due to direct actions on 5-HT receptors. 6 The evidence presented supports the hypothesis that LSD-like psychotomimetics act by an antagonism of 5-HT in the lower brain stem, and is not compatible with the suggestion that the psychotomimetic action of these drugs is related to 5-HT receptor stimulation.

Effects of Methysergide on the Cough Reflex

“…Methysergide is a competitive inhibitor of serotonin receptor (9) and is highly effective in antagonizing central serotonin (10,11). In the present study, methysergide inhibited the antitussive effect of dextromethorphan by more than 60%, substantiating the con tention that serotonin may be the responsible neurotransmitter in the central mechanisms of the cough reflex.…”

The action of serotonin in the rat hippocampal slice preparation.

“…It is contained in the raphe nuclei of the brain stem which project to the rest of the brain and spinal cord. With the exception of a few studies (Barasi & Roberts, 1974;Bradley & Briggs, 1974;Couch, 1976;Roberts & Straughan, 1967), the effects of ionophoretically administered 5-HT on neurones in the mammalian central nervous system are reported to be mainly depressant (Bloom, Hoffer, Siggins, Barker & Nicoll, 1972;Phillis, Tebecis & York, 1967;Roberts & Straughan, 1967;Sastry & Phillis, 1977;Wang & Aghajanian, 1977;Weight & Salmoiraghi, 1968). Little is known about the mechanism of action of 5-HT in the mammalian brain.…”

5‐Methoxy‐N,N‐dimethyltryptamine‐induced analgesia is blocked by α‐adrenoceptor antagonists in rats

“…Systemic administration of 5-methoxy-N,N-dimethyltryptamine (5-MeODMT), a 5-HT agonist (Anden et al, 1971;Bradley & Briggs, 1974) produces a dose-dependent analgesia (Berge et al, 1980). Recent experimental results, though, indicate that the analgesia produced by 5-HT and 5-MeODMT is dependent on an intact descending NA system (Archer et al, 1985a,b, Minor et al, 1985.…”