PAROXETINE AS AN INVIVO INDICATOR OF 3,4-METHYLENEDIOXYMETHAMPHETAMINE NEUROTOXICITY - A PRESYNAPTIC SEROTONERGIC POSITRON EMISSION TOMOGRAPHY LIGAND

The present study sought to determine whether [3H]paroxetine, a potent and selective inhibitor of serotonin uptake in vitro, could be used to label the serotonin transporter in the rat brain in vivo such that it might be employed to develop a presynaptic serotonergic positron emission tomography ligand. Tritium labeled paroxetine was administered intravenously to rats by means of tail vein injection. Four hours later, specific [3H]paroxetine binding was determined by subtracting non-specific binding in the cerebellum from total binding in other brain regions of interest. The distribution of specific [3H]paroxetine binding paralleled the distribution of serotonin uptake sites in all brain regions examined. Pretreatment with serotonin re-uptake inhibitors (citalopram or sertraline) reduced in vivo specific [3H]paroxetine binding by as much as 99%. Specific in vivo [3H]paroxetine binding was further characterized through the use of 5,7-dihydroxytryptamine (5,7-DHT), a known serotonergic neurotoxin. 5,7-DHT (200 μg, i.c.v.) caused a marked reduction in specific [3H]paroxetine binding, and induced a prolonged depletion of regional brain serotonin. In a final study, the feasibility of using in vivo [3H]paroxetine binding as an indicator of serotonergic damage induced by another neurotoxin (3,4-methylenedioxymethamphetamine, MDMA) was tested. MDMA-treated rats showed a profound reduction in in vivo [3H]paroxetine binding, along with a lasting depletion of regional brain serotonin. These results demonstrate that [3H]paroxetine can be used to label serotonin uptake sites in rat rat brain in vivo, and that the damage induced by serotonergic neurotoxins can be detected using in vivo [3H]paroxetine binding as an indicator. Paroxetine (or one of its derivatives) therefore holds promise as a PET ligand for studying serotonergic neurons in the living human brain in health as well as after neurotoxic injury. © 1990.