Study on the neuroprotective effect of fluoxetine against MDMA-induced neurotoxicity on the serotonin transporter in rat brain using micro-PET.
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.
Li
I-Hsun
IH
Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan.
Huang
Wen-Sheng
WS
Shiue
Chyng-Yann
CY
Huang
Ya-Yao
YY
Liu
Ren-Shyan
RS
Chyueh
San-Chong
SC
Hu
Shih-Hsiung
SH
Liao
Mei-Hsiu
MH
Shen
Lie-Hang
LH
Liu
Jiang-Chuan
JC
Ma
Kuo-Hsing
KH
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
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