Antagonism of 5‐hydroxytryptamine by LSD 25 in the central nervous system: a possible neuronal basis for the actions of LSD 25

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.

Study at a glance

Abstract

Summary 5‐Hydroxytryptamine (5‐HT), acetylcholine (ACh), noradrenaline (NA), glutamate, d , l ‐homocysteic acid (DLH), glycine and γ‐aminobutyric acid (GABA) were applied to single neurones in the brain stem of decerebrate cats by microiontophoresis. The abilities of d ‐lysergic acid diethylamide tartrate (LSD 25), methysergide maleate (UML 491) and 2‐bromo‐lysergic acid diethylamide (BOL 148) to antagonize the actions of these compounds were studied. LSD 25 antagonized 5‐HT excitation of single neurones when applied iontophoretically or administered intravenously. LSD 25 also antagonized glutamate excitation of neurones which could be excited by 5‐HT. Inhibitory effects of 5‐HT, the action of glutamate on neurones which could be inhibited by 5‐HT and the actions of all the other compounds tested were unaffected by LSD 25. Iontophoretically applied UML 491 was also a specific antagonist to 5‐HT and glutamate excitation but was less potent than LSD 25, and BOL 148 rarely exhibited antagonism. It is suggested that antagonism to 5‐HT and glutamate excitation of brain stem neurones may be the basis of the psychotomimetic action of LSD 25. It is also suggested that there may be similarities in the mechanisms by which 5‐HT and glutamate produce excitation where they act on the same neurone.