Hallucinogenic drugs such as lysergic acid diethylamide (LSD) and (plus/minus)-3,4-methylene-dioxymethamphetamine (MDMA) are abused in our society. The hallucinogenic indole-alkylamines LSD and 5-methoxy-N, N- dimethyltryptamine (5-MeODMT), and the phenalkylamines MDMA and (plus/minus)-2,5-dimethoxy-4-methylamphetamine (DOM) interact with the 5- hydroxytryptamine (5-HT) neuronal systems of the brain. The interactions of these drugs with 5-HT systems have been under investigation for over 20 years and have provided new opportunities for advancing our understanding of the actions of the hallucinogens. The method of in vivo microdialysis for simultaneous measurement of the extracellular levels of 5-HT and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) in discrete areas of the forebrain will allow us to determine the effects of hallucinogenic drugs on 5-HT neurons activated by electrical stimulation of the dorsal and median raphe nuclei. Microdialysis probes will be implanted into medial prefrontal cortex, striatum, nucleus accumbens, hippocampus and habenular nuclei. These forebrain sites are primary areas of termination for 5-HT neuronal pathways originating in the midbrain raphe. Behavioral discrimination will be used to provide behavioral data to correlate with neurochemical data. Animals will be trained to discriminate electrical stimulation of the dorsal or median raphe nucleus from non-stimulation. Agonists and antagonists at subtypes of 5-HT receptors will be examined for their effects on behavioral discrimination as well as brain neurochemistry following electrical stimulation of the raphe nuclei. The effects of LSD, 5-MeODMT, DOM and MDMA will be examined in these paradigms to determine the differential roles of the raphe nuclei and subtypes of 5-HT receptors in the actions of these drugs. Changes in the release of 5-HT in brain areas will be correlated with the results of behavioral experiments. These studies will develop the experimental basis to examine the neurochemical and behavioral actions of hallucinogens on both electrical and drug-induced activation of the major forebrain 5-HT nuclei, the dorsal and median raphe. These studies will also allow important insight into the functional nature of the 5-hydroxytryptamine neuronal pathways in conscious animals and will lead to a better understanding of the mechanisms and sites of action of these hallucinogenic drugs of abuse.
