The aim of the proposed research is to assess the neuronal mechanisms underlying certain behavioral effects of indole- and phenylalkylamine hallucinogens (e.g., LSD [d-lysergic acid diethylamide] and mescaline [3,4,5-trimethoxyphenylthylamine]), central nervous system (CNS) stimulants (e.g., d-amphetamine and cocaine) and the so-called """"""""designer"""""""" drugs, MDA (3,4-methylenedioxyamphetamine) and MDMA (3,4- methylenedioxymethamphetamine), which appear to have both hallucinogenic and stimulant properties. Our principle behavioral procedure will continue to be drug discrimination which has been of considerable value in advancing our understanding of drug actions and has served as an excellent, if not unique animal model of the subjective effects of hallucinogenic and related substances in humans. The reasons we continue to use this admittedly difficult and time-consuming assay include the fact that it is pharmacologically specific in that substitution of a novel compound for a training drug (generalization of a drug """"""""cue"""""""") usually reflects common mechanisms of action rather than simply psychoactive effects and blockade of the stimulus properties of a training or test drug (during a combination test) normally requires that the """"""""agonist"""""""" and """"""""antagonist"""""""" compounds have similar receptor actions. In addition, drug discrimination is sensitive in that it is able to reliably assess the behavioral effects of very small doses of drugs such as LSD and lisuride and reliable, possibly because it uses response choice rather than rate as its primary dependent variable and thereby avoids confounds caused by unconditioned effects of test or training drugs on motor behavior. Finally, drug discrimination results correlate highly with neurochemical (e.g., receptor binding) results; thus, this procedure has acquired respectability as a pharmacological assay by confirming behavioral (in vivo) relevance to in vitro or ex vivo findings.
