title: Chronic methamphetamine administration causes differential regulation of transcription factors in the rat midbrain.
abstract: Methamphetamine (METH) is an addictive and neurotoxic psychostimulant widely abused in the USA and throughout the world. When administered in large doses, METH can cause depletion of striatal dopamine terminals, with preservation of midbrain dopaminergic neurons. Because alterations in the expression of transcription factors that regulate the development of dopaminergic neurons might be involved in protecting these neurons after toxic insults, we tested the possibility that their expression might be affected by toxic doses of METH in the adult brain. Male Sprague-Dawley rats pretreated with saline or increasing doses of METH were challenged with toxic doses of the drug and euthanized two weeks later. Animals that received toxic METH challenges showed decreases in dopamine levels and reductions in tyrosine hydroxylase protein concentration in the striatum. METH pretreatment protected against loss of striatal dopamine and tyrosine hydroxylase. In contrast, METH challenges caused decreases in dopamine transporters in both saline- and METH-pretreated animals. Interestingly, METH challenges elicited increases in dopamine transporter mRNA levels in the midbrain in the presence but not in the absence of METH pretreatment. Moreover, toxic METH doses caused decreases in the expression of the dopamine developmental factors, Shh, Lmx1b, and Nurr1, but not in the levels of Otx2 and Pitx3, in saline-pretreated rats. METH pretreatment followed by METH challenges also decreased Nurr1 but increased Otx2 and Pitx3 expression in the midbrain. These findings suggest that, in adult animals, toxic doses of METH can differentially influence the expression of transcription factors involved in the developmental regulation of dopamine neurons. The combined increases in Otx2 and Pitx3 expression after METH preconditioning might represent, in part, some of the mechanisms that served to protect against METH-induced striatal dopamine depletion observed after METH preconditioning.
authors.affiliation: Molecular Neuropsychiatry Research Branch, DHHS/NIH/NIDA Intramural Research Program, Bethesda, Maryland, United States of America.
authors.forename: Irina N
authors.initials: IN
authors.lastname: Krasnova
authors.forename: Bruce
authors.initials: B
authors.lastname: Ladenheim
authors.forename: Amber B
authors.initials: AB
authors.lastname: Hodges
authors.forename: Nora D
authors.initials: ND
authors.lastname: Volkow
authors.forename: Jean Lud
authors.initials: JL
authors.lastname: Cadet
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001831:Body Temperature / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D004298:Dopamine / Q000378:metabolism; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D060850:LIM-Homeodomain Proteins; D008297:Male; D008636:Mesencephalon / Q000187:drug effects* / Q000378:metabolism*; D008694:Methamphetamine / Q000494:pharmacology*; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2 / Q000235:genetics / Q000378:metabolism; D051857:Otx Transcription Factors / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics / Q000378:metabolism
chemical_list: D053823:Hedgehog Proteins; D018398:Homeodomain Proteins; C112149:LIM homeobox transcription factor 1 beta; D060850:LIM-Homeodomain Proteins; C539884:Nr4a2 protein, rat; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D051857:Otx Transcription Factors; C546888:Shh protein, rat; D014157:Transcription Factors; C433629:homeobox protein PITX3; D008694:Methamphetamine; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine