The present project is comprised of studies in rodents, non-human primates and humans. The neurotoxic potential of a variety of amphetamine analogs, including (+/-) 3,4-methylenedioxymethamphetamine, methamphetamine, fenfluramine and methcathinone, is first determined in animals, and the utility of various biological assays for the detection of neurotoxicity are determined. Methods used include direct neurochemical measures of monoamines, their metabolites, their synthetic enzymes, and their transporters. When indicated, anatomical studies using immunofluorescent techniques are also conducted, as are positron emission tomography (PET) studies using radiopharmaceuticals that selectively label monoaminergic transporters. Studies in humans are designed to determine whether neurotoxicity seen in animals is also seen in humans exposed to these drugs, and if so, the functional consequences of this damage. Methods utilized include cerebrospinal fluid (CSF) measures of 5-hydroxyindoleacetic acid (5-HIAA), PET studies, pain testing, sleep studies, neuroendocrine challenges, cognitive testing, and a variety of psychiatric tests. To date, all of the above compounds have been shown to be neurotoxic to serotonin neurons, dopamine neurons, or both, in rodents and non-humans primates. CSF studies and PET studies have both been shown to be valid methods for detecting monoaminergic neurotoxicity. In humans, it has been determined that MDMA users have selective decreases in CSF 5-HIAA, blunted neuroendocrine and behavioral responses to m-CPP, a serotonin agonist, decreased serotonin transporters as visualized by PET, alterations in sleep architecture. and decrements in a cognitive task requiring sustained attention and arithmetic calculation. Methamphetamine and methcathinone users have been found to have significant decreases in the dopamine transporter, as visualized by PET. Ongoing studies are aimed at extending these findings.
