Molecular Pharmacology, Vol 12, 620-630, Copyright © 1976 by the American Society for Pharmacology and Experimental Therapeutics

Stereospecific Receptor Sites for d-Lysergic Acid Diethylamide in Rat Brain: Effects of Neurotransmitters, Amine Antagonists, and Other Psychotropic Drugs

¹ Department of Psychiatry, The University of Chicago, Chicago, Illinois 60637

A method in vitro designed to determine specifically the stereospecificity of tissue receptor sites was used to study the characteristics of d-lysergic acid diethylamide (LSD) binding by rat brain particulates and the effects of selectively chosen drugs. There is a high- and a low-affinity binding, and both are stereospecific. The high-affinity binding is saturable (half-saturation at 4 nM) and shows definite regional and subcellular differences. The highest binding relative to protein content occurs in the striatum regionally and in microsomal fractions subcellularly. The subcellular distribution data also suggest that the d-LSD acceptor substance need not be confined to the neuronal soma or terminal membrane. The effects of related hallucinogens, neurotransmitters, serotonin (5-HT) and dopamine antagonists, and other drugs were studied to help determine whether central 5-HT receptors are identical with a site of LSD binding. Of the drugs tested, methiothepin was most effective in blocking the high-affinity, stereospecific binding of d-LSD. The pattern of drug effects suggests that the high-affinity, stereospecific binding site on brain membranes may not be identical with a 5-HT or dopamine receptor, but that LSD and nonpsychotomimetic congeners can bind to such receptors while simultaneously binding to one or more other points on the membrane in the immediate vicinity of the receptor. This is consistent with the view that LSD can act either agonistically or antagonistically at central 5-HT, and possibly dopamine, receptors in vivo.

Note:
ACKNOWLEDGMENTS We gratefully acknowledge the excellent technical assistance of Susan Homan and Francisco Ortiz. We also thank Dr. Nicholas Lenn for electron micrographs and Dr. Robert Dinerstein, Department of Pharmacological and Physiological Sciences, University of Chicago, for his help in the data analysis and in the construction of the molecular models and drawings.