title: Sex differences in methamphetamine toxicity in mice: effect on brain dopamine signaling pathways.
abstract: Male mice were reported to display greater methamphetamine-induced neurotoxicity than females. The present study evaluated the involvement of phosphatidylinositol-3 kinase (PI3K)/Akt and extracellular signal-regulated kinase (ERK1/2) pathways in this sex-dependent methamphetamine toxicity. Intact female and male mice were administered methamphetamine (20 or 40mg/kg) and euthanized a week later. Dopamine transporter (DAT) and vesicular monoamine transporter 2 (VMAT2) autoradiography in the lateral striatum showed a greater sensitivity in male mice treated with 20mg/kg methamphetamine compared to female mice. Striatal dopamine concentration and DAT autoradiography showed a more extensive depletion in male mice given 40mg/kg methamphetamine compared to female mice. Mice administered 40mg/kg methamphetamine showed no sex difference in striatal VMAT2 autoradiography. In the substantia nigra, DAT specific binding was decreased only in male mice treated with 40mg/kg methamphetamine and DAT mRNA levels decreased in methamphetamine-treated female and male mice. Methamphetamine-treated male mice presented a dose-dependent decrease of VMAT2 mRNA levels. Methamphetamine reduced insulin-like growth factor 1 receptor levels in females at both methamphetamine doses tested whereas it elevated G protein-coupled estrogen receptor 1 (GPER1) only in male mice. Phosphorylated Akt levels decreased only in male mice treated with 40mg/kg methamphetamine. Glycogen synthase kinase 3β levels were reduced in male mice at both methamphetamine doses tested and in females receiving 40mg/kg. Bcl-2 levels were increased in male mice treated with methamphetamine, whereas ERK1/2 and BAD levels were unchanged. These results implicate some of the signaling pathways associated with the sex differences in methamphetamine-induced toxicity.
authors.affiliation: Molecular Endocrinology and Genomic Research Center, Centre de recherche du CHUQ (CHUL), Quebec City, Quebec, G1V 4G2, Canada.
authors.forename: Mélanie
authors.initials: M
authors.lastname: Bourque
authors.forename: Bin
authors.initials: B
authors.lastname: Liu
authors.forename: Dean E
authors.initials: DE
authors.lastname: Dluzen
authors.forename: Thérèse
authors.initials: T
authors.lastname: Di Paolo
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D004298:Dopamine / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism; D018765:Dopamine Uptake Inhibitors / Q000378:metabolism / Q000494:pharmacology; D005260:Female; D008297:Male; D008694:Methamphetamine / Q000494:pharmacology / Q000633:toxicity*; D051379:Mice; D009434:Neural Pathways / Q000187:drug effects / Q000378:metabolism; D020258:Neurotoxicity Syndromes / Q000378:metabolism / Q000503:physiopathology; D011485:Protein Binding; D012727:Sex Characteristics; D015398:Signal Transduction / Q000187:drug effects; D013747:Tetrabenazine / Q000378:metabolism / Q000493:pharmacokinetics; D050493:Vesicular Monoamine Transport Proteins / Q000378:metabolism
chemical_list: D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; C493453:Slc18a2 protein, mouse; D050493:Vesicular Monoamine Transport Proteins; D008694:Methamphetamine; D004298:Dopamine; D013747:Tetrabenazine