Analyzing mechanism(s) of hallucinogenic drug action with drug discrimination procedures

Abstract

Some of the advantages of using drug discrimination (DD) procedures to analyze the mechanisms of action of hallucinogenic and related drugs were illustrated by reviewing research with lysergic acid diethylamide (LSD). Because they ensure that drug-induced alterations in interoceptive “state” become biologically meaningful “cues,” these procedures are reliable, robust, sensitive and specific. With reference to LSD, many DD experiments suggest: (1) that while hallucinogens substitute for (mimic) LSD (in rats), such substitution does not predict hallucinogenic potency (in humans) but does predict similarities in mechanism(s) of action; (2) the behavioral (in vivo) effects of LSD, unlike those of some of its congeners, are mediated primarily by central, serotonergic (5-HT) neuronal mechanism although LSD may also have (secondary) dopamine (DA) agonist properties; (3) both the locus and the nature of these LSD-5-HT interactions are unclear: cells arising from B-7, B-8 and B-9 regions of the dorsal-medial raphe may be involved; pretreatment with agents that deplete 5-HT and increase the stereospecific binding of 3H-LSD in vitro (p-chlorophenylalanine; 5,7-dihydroxytryptamine) enhance sensitivity to LSD in vivo.