3,4-Methylenedioxymethamphetamine (MDMA), a popular recreational drug of abuse, and fenfluramine, and anorectic agent used in this country and abroad, are highly toxic to serotonergic neurons in the brains of a variety of experimental animals, including non-human primates. Currently, there are no methods for non-invasively detecting such as neural damage in living animals or humans. development of a PET ligand selective for serotonergic axons hold promise for achieving this end. This study will confirm preliminary in vivo data demonstrating that 3 H- paroxetine selectively labels the serotonin (5HT) uptake site on serotonergic axon terminals, synthesize positron emitting paroxetine, demonstrate its ability to selectively label the serotonin uptake site in vivo and validate its utility as a diagnostic probe. This will be done first in animals by showing that positron emitting paroxetine can be successfully employed to detect clinically inapparent serotonergic damage in 5,7-dihydroxytryptamine (5,7-DHT)-treated animals. Having established this, the present research will employ the PET ligand to detect serotonergic damage in living baboons whose central 5HT neurons have previously been lesioned with MDMA or fenfluramine. Finally, these studies will assess the sensitivity of the PET method for detecting partial serotonergic damage and evaluate the feasibility of using PET to study 5HT neurons over time in MDMA- treated baboons. The latter study should yield valuable information regarding the fate of damaged 5HT axons in MDMA-treated primates, and shed light on the influence of the aging process of MDMA neurotoxicity. The long-term goals of this research are to develop a novel PET label selective for the presynaptic element of 5HT neurons with an eye toward using the ligand as a diagnostic probe in humans, and also as an experimental tool for investigating serotonergic function in the living human brain during both health and disease. In particular, these studies seek to develop a PET ligand that can be used to evaluate humans previously exposed to MDMA or fenfluramine, as these individuals are at high risk for having sustained 5HT neural damage. Longitudinal studies of these subjects made possible by PET may yield valuable insights regarding the functional role of serotonin in the human brain, and should help define the long-term public health consequences of MDMA and fenfluramine exposure.
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