title: Sex and temporally-dependent effects of methamphetamine toxicity on dopamine markers and signaling pathways.
abstract: Methamphetamine induces a greater neurodegenerative effect in male versus female mice. In order to investigate this sex difference we studied the involvement of Akt and extracellular signal-regulated kinase (ERK1/2) in methamphetamine toxicity as a function of time post-treatment (30 min, 1 and 3 days). Methamphetamine-induced decreases in dopamine concentrations and dopamine transporter (DAT) specific binding in the medial striatum were similar in female and male mice when evaluated 1 day post-methamphetamine (40 mg/kg). At 3 days post-methamphetamine, striatal dopamine concentration and DAT specific binding continued to decline in males, whereas females showed a recovery with increases in dopamine content and DAT specific binding in medial striatum at day 3 versus day 1 post-methamphetamine. The reduction in striatal vesicular monoamine transporter 2 specific binding observed at 1 and 3 days post-methamphetamine showed neither a sex- nor temporal-dependent effect. Under the present experimental conditions, methamphetamine treatments had modest effects on dopamine markers measured in the substantia nigra. Proteins assessed by Western blots showed similar reductions in both female and male mice for DAT proteins at 1 and 3 days post-methamphetamine. An increase in the phosphorylation of striatal Akt (after 1 day), glycogen synthase kinase 3β (at 1 and 3 days) and ERK1/2 (30 min post-methamphetamine) was only observed in females. Striatal glial fibrillary acidic protein levels were augmented in both females and males at 3 days post-methamphetamine. These results reveal some of the sex- and temporally-dependent effects of methamphetamine toxicity on dopaminergic markers and suggest some of the signaling pathways associated with these responses.
authors.affiliation: Molecular Endocrinology and Genomic Research Center, Centre de recherche du CHUQ (CHUL), Quebec City, Quebec, Canada.
authors.forename: Mélanie
authors.initials: M
authors.lastname: Bourque
authors.forename: Dean E
authors.initials: DE
authors.lastname: Dluzen
authors.forename: Thérèse
authors.initials: T
authors.lastname: Di Paolo
mesh_terms: D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000502:physiology*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism*; D005260:Female; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D008297:Male; D008694:Methamphetamine / Q000633:toxicity*; D051379:Mice; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D012727:Sex Characteristics; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013997:Time Factors
chemical_list: D015415:Biomarkers; D050483:Dopamine Plasma Membrane Transport Proteins; D015102:3,4-Dihydroxyphenylacetic Acid; D008694:Methamphetamine; D051057:Proto-Oncogene Proteins c-akt; D004298:Dopamine