title: Study on the neuroprotective effect of fluoxetine against MDMA-induced neurotoxicity on the serotonin transporter in rat brain using micro-PET.
abstract: 3, 4-Methylenedioxymethamphetamine (MDMA, "ecstasy") has toxic effects on serotonergic neurons in the brain. Our aim was to determine whether N,N-dimethyl-2-(2-amino-4-[(18)F]-fluorophenylthio) benzylamine (4-[(18)F]-ADAM; a serotonin transporter imaging agent) and micropositron emission tomography (micro-PET) can be used to examine in vivo the effect of fluoxetine on MDMA-induced loss of serotonin transporters in rat brain. Male Sprague-Dawley rats were injected with fluoxetine [1 dose, 5 mg/kg, subcutaneously (s.c.)] followed by MDMA (twice a day for 4 consecutive days, 10 mg/kg, s.c.). Micro-PET with 4-[(18)F]-ADAM was performed on days 4, 10, 17, 24, and 31. In addition, the time course of occupancy by fluoxetine at 4-[(18)F]-ADAM sites was measured. Specific 4-[(18)F]-ADAM uptake ratios (SURs) were calculated from the micro-PET imaging data for various brain regions. Immunohistochemistry was performed 7 days after the last micro-PET scan. From day 4 to day 31, SURs were markedly decreased (by approximately 55-75% compared to control values) in all brain regions in MDMA-treated rats. The effect of MDMA was markedly attenuated (approximately 30-50%) by fluoxetine. The fluoxetine-induced decrease in uptake in different brain regions was 40-75% at 90-min postinjection, and this decrease returned to baseline values in most brain regions by day 31. The distribution and intensity of serotonin transporter (SERT) immunostaining in the brain paralleled the PET imaging results, suggesting that a single dose of fluoxetine provides long-lasting protection against MDMA-induced loss of SERT and that such neuroprotection is detectable in vivo by 4-[(18)F]-ADAM micro-PET.
authors.affiliation: Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan.
authors.forename: I-Hsun
authors.initials: IH
authors.lastname: Li
authors.forename: Wen-Sheng
authors.initials: WS
authors.lastname: Huang
authors.forename: Chyng-Yann
authors.initials: CY
authors.lastname: Shiue
authors.forename: Ya-Yao
authors.initials: YY
authors.lastname: Huang
authors.forename: Ren-Shyan
authors.initials: RS
authors.lastname: Liu
authors.forename: San-Chong
authors.initials: SC
authors.lastname: Chyueh
authors.forename: Shih-Hsiung
authors.initials: SH
authors.lastname: Hu
authors.forename: Mei-Hsiu
authors.initials: MH
authors.lastname: Liao
authors.forename: Lie-Hang
authors.initials: LH
authors.lastname: Shen
authors.forename: Jiang-Chuan
authors.initials: JC
authors.lastname: Liu
authors.forename: Kuo-Hsing
authors.initials: KH
authors.lastname: Ma
mesh_terms: D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000378:metabolism; D005473:Fluoxetine / Q000494:pharmacology*; D007150:Immunohistochemistry; D008297:Male; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000633:toxicity*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010784:Photomicrography; D049268:Positron-Emission Tomography / Q000379:methods; D051381:Rats; D017207:Rats, Sprague-Dawley; D018490:Serotonin Agents / Q000633:toxicity*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism*; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology; D013997:Time Factors
chemical_list: D005473:Fluoxetine; D018817:N-Methyl-3,4-methylenedioxyamphetamine; D018696:Neuroprotective Agents; D018490:Serotonin Agents; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors; C493232:Slc6a4 protein, rat