Further studies on the mode of action of psychotomimetic drugs: antagonism of the excitatory actions of 5-hydroxytryptamine by methylated derivatives of tryptamine.
1 The actions of 5-methoxytryptamine (5-MeOT), N,N-dimethyltryptamine (DMT), 5-hydroxy-N,N-dimethyltryptamine (bufotenine, 5-HODMT) and 5-methoxy-N,N-dimethyltryptamine (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.
D000109:Acetylcholine / Q000037:antagonists & inhibitors; D000818:Animals; D001933:Brain Stem / Q000187:drug effects; D002415:Cats; D018691:Excitatory Amino Acid Antagonists; D005260:Female; D010134:Fenclonine / Q000008:administration & dosage; D006213:Hallucinogens / Q000494:pharmacology*; D007478:Iontophoresis; D008238:Lysergic Acid Diethylamide / Q000037:antagonists & inhibitors; D008297:Male; D004130:N,N-Dimethyltryptamine / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects; D009638:Norepinephrine / Q000037:antagonists & inhibitors; D011292:Premedication; D051381:Rats; D012110:Reserpine / Q000008:administration & dosage; D012702:Serotonin Antagonists; D014363:Tryptamines / Q000494:pharmacology*
D018691:Excitatory Amino Acid Antagonists; D006213:Hallucinogens; D012702:Serotonin Antagonists; D014363:Tryptamines; D012110:Reserpine; D008238:Lysergic Acid Diethylamide; D000109:Acetylcholine; D010134:Fenclonine; D004130:N,N-Dimethyltryptamine; D009638:Norepinephrine