Lysergic acid diethylamide (LSD) antagonizes excitation produced by serotonin (5-HT) and glutamate on certain brain stem neurons in decerebrate cats. When applied directly or intravenously, LSD blocked 5-HT-induced excitation and also blocked glutamate excitation on neurons that could be excited by 5-HT. However, LSD did not affect inhibitory actions of 5-HT, glutamate effects on neurons inhibited by 5-HT, or actions of acetylcholine, noradrenaline, homocysteic acid, glycine, or GABA. Methysergide was a weaker antagonist, and 2-bromo-LSD rarely showed antagonism. The authors propose that antagonism to 5-HT and glutamate excitation may underlie LSD's psychotomimetic effects.
Three psychotomimetic tryptamines—DMT, bufotenine, and 5-MeODMT—specifically blocked serotonin-induced excitations of single neurons in the brain stem of anesthetized rats and decerebrate cats, similar to LSD. The non-psychotomimetic 5-MeOT had no such antagonistic effect. Unlike LSD, the psychotomimetic tryptamines rarely blocked glutamate effects, suggesting separate but spatially close serotonin and glutamate receptors. These tryptamines could mimic serotonin's actions on neurons, but the psychotomimetic ones were less potent than 5-MeOT. The serotonin-mimicking effects were not due to serotonin release, as they persisted after depletion of serotonin by p-chlorophenylalanine or reserpine, indicating direct action on serotonin receptors. The findings support the hypothesis that LSD-like psychotomimetics act by antagonizing serotonin in the lower brain stem, not by stimulating serotonin receptors.