Lack of effect of testosterone and dihydrotestosterone compared to 17beta-oestradiol in 1-methyl-4-phenyl-1,2,3,6, tetrahydropyridine-mice.
Previous work from our laboratory has demonstrated prevention of 1-methyl-4-phenyl-1,2,3,6, tetrahydropyridine (MPTP)-induced striatal dopamine depletion in C57Bl/6 mice by 17beta-oestradiol, progesterone and raloxifene. The activity of androgenic compounds in MPTP mice has received less attention and was the object of the present investigation. The effects of 17beta-oestradiol (2 microg/day), testosterone (100 microg/day) and dihydrotestosterone (DHT) (2 microg/day or 100 microg/day) were studied during 5 days before and after an acute treatment of four MPTP (10 mg/kg) injections in male C57Bl/6 mice. Striatal concentrations of dopamine and its metabolites dihydroxyphenylacetic acid and homovanillic acid were measured by high-performance liquid chromatography. MPTP mice treated with saline showed large decreases in dopamine and its metabolites compared to control mice. 17beta-oestradiol partially spared this decrease whereas testosterone and DHT did not. Striatal specific binding to the dopamine transporter (DAT) and to the vesicular monoamine transporter (VMAT2) were measured using [125I] RTI-121 and [3H] dihydrotetrabenazine autoradiography, respectively. As with striatal dopamine concentrations, MPTP treatment caused a decrease in DAT and VMAT2 specific binding. 17beta-oestradiol partially spared this decrease, whereas androgens did not. In the substantia nigra, DAT mRNA was measured by in situ hybridization. MPTP treatment induced a significant, but smaller decrease in substantia nigra DAT mRNA than striatal DAT protein. In addition, 17beta-oestradiol completely prevented the MPTP-induced decrease of DAT mRNA, whereas androgens did not. The present results show that androgens are unable to protect against MPTP-induced dopaminergic toxicity.
Ekue
A
A
Molecular Endocrinology and Oncology Research Center, Laval University Medical Center, CHUL and Faculty of Pharmacy, Laval University, Quebec, Canada.
Boulanger
J-F
JF
Morissette
M
M
Di Paolo
T
T
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D001345:Autoradiography; D003042:Cocaine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D013196:Dihydrotestosterone / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins; D004958:Estradiol / Q000494:pharmacology*; D012739:Gonadal Steroid Hormones / Q000494:pharmacology*; D006719:Homovanillic Acid / Q000378:metabolism; D017403:In Situ Hybridization; D007457:Iodine Radioisotopes; D020267:MPTP Poisoning / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins; D009479:Neuropeptides; D012333:RNA, Messenger / Q000032:analysis; D013739:Testosterone / Q000494:pharmacology*; D013747:Tetrabenazine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D014316:Tritium; D050492:Vesicular Biogenic Amine Transport Proteins; D050493:Vesicular Monoamine Transport Proteins
D050483:Dopamine Plasma Membrane Transport Proteins; D012739:Gonadal Steroid Hormones; D007457:Iodine Radioisotopes; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D009479:Neuropeptides; D012333:RNA, Messenger; C493453:Slc18a2 protein, mouse; C493215:Slc6a3 protein, mouse; D050492:Vesicular Biogenic Amine Transport Proteins; D050493:Vesicular Monoamine Transport Proteins; D013196:Dihydrotestosterone; D014316:Tritium; D015102:3,4-Dihydroxyphenylacetic Acid; C079213:RTI 121; C032811:dihydrotetrabenazine; D013739:Testosterone; D004958:Estradiol; D003042:Cocaine; D004298:Dopamine; D006719:Homovanillic Acid; D013747:Tetrabenazine