In animals, the recreational drug 3,4-methylenedioxymethamphetamine (MDMA) is a documented serotonin (5-HT) neurotoxin. Whether or not MDMA us also neurotoxic in humans is not known, but there is recent evidence that it is, i.e., human MDMA users have lower concentrations of the 5-HT metabolite 5-HIAA in their cerebrospinal fluid (CSF) than controls. The difficulty in assessing the neurotoxic potential of MDMA in humans stems largely from the fact that there are not direct methods for investigating neurons in the living human brain. Positron emission tomography (PET), when used in conjunction with a radioligand specific for the 5-HT neuron, is an imaging technique that could be used to study that status of 5-HT neurons in humans druing life. Indeed, preliminary observations suggest that PET imaging with the newly developed 5-HT transporter ligand [11C]McN-5652 is useful for detecting brain 5-HT deficits in MDMA lesioned baboons. The overall goal of the project is to confirm this finding and extend it to humans. To achieve this goal, two series of studies are proposed, one in baboons and the other in humans. In preclinical studies, baboons will be lesioned with either MDMA or 2'-NH2-MPTP, MPTP analog that, when administered with desmethylimipramine (DMI), is highly and selectively toxic to the brain 5- HT neurons. Baboons lesioned with MDMA which is known to damage brain 5-HT systems in the entire forebrain, will be used for """"""""between subjects"""""""" comparisons; baboons lesioned with 2'-NH2-MPTP, which should permit unilateral lesions of brain 5-HT systems, will be used for """"""""within subjects"""""""" comparisons. At 36 and 72 weeks after lesioning, the animals will undergo PET studies with [11C]McN-5652 and lumbar punctures for CSF 5-HIAA determinations. The animals will then be sacrificed for direct determination of tissue 5-HT axonal markers. These studies will offer the unique opportunity to study the relationship between alterations in specific [11C]McN-5652 binding measured in vivo by means of PET and changes in tissue 5HT neuronal markers, i.e., 5-HT, 5-HIAA, [3H]citalopram binding sites, measured directly in postmortem tissue of the same animals. In a second set of studies, humans with an extensive history of MDMA use, but drug-free for at least four weeks, will undergo PET and CSF studies identical to those in baboons. Results obtained in MDMA users (MDMA group, n=18) will be compared to those obtained in individuals who have used drugs other than MDMA (non-MDMA group, n=18), as well as to those obtained in subjects without a history of drug use or dependence (non- drug group, n=18). The purpose of these studies is to further assess the status of central 5-HT neurons in humans after MDMA exposure, and to extend to humans the observation that in nonhuman primates PET imaging with [11C]McN-5652 is useful for detecting MDMA-induced 5-HT neural injury during life. The long-term goals of this project are: 1) to further validate the usefulness of [11C]McN-5652 for studying 5-HT neurons in the living human brain with PET; and 2) to better define the neurotoxic potential of MDMA in humans.
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