title: Decreased level of Nurr1 in heterozygous young adult mice leads to exacerbated acute and long-term toxicity after repeated methamphetamine exposure.
abstract: The abuse of psychostimulants, such as methamphetamine (METH), is prevalent in young adults and could lead to long-term adaptations in the midbrain dopamine system in abstinent human METH abusers. Nurr1 is a gene that is critical for the survival and maintenance of dopaminergic neurons and has been implicated in dopaminergic neuron related disorders. In this study, we examined the synergistic effects of repeated early exposure to methamphetamine in adolescence and reduction in Nurr1 gene levels. METH binge exposure in adolescence led to greater damage in the nigrostrial dopaminergic system when mice were exposed to METH binge later in life, suggesting a long-term adverse effect on the dopaminergic system. Compared to naïve mice that received METH binge treatment for the first time, mice pretreated with METH in adolescence showed a greater loss of tyrosine hydroxylase (TH) immunoreactivity in striatum, loss of THir fibers in the substantia nigra reticulata (SNr) as well as decreased dopamine transporter (DAT) level and compromised DA clearance in striatum. These effects were further exacerbated in Nurr1 heterozygous mice. Our data suggest that a prolonged adverse effect exists following adolescent METH binge exposure which may lead to greater damage to the dopaminergic system when exposed to repeated METH later in life. Furthermore, our data support that Nurr1 mutations or deficiency could be a potential genetic predisposition which may lead to higher vulnerability in some individuals.
authors.affiliation: National Institute on Drug Abuse, Intramural Research Program, Baltimore, Maryland, United States of America. luoy@mail.nih.gov
authors.forename: Yu
authors.initials: Y
authors.lastname: Luo
authors.forename: Yun
authors.initials: Y
authors.lastname: Wang
authors.forename: Serena Y
authors.initials: SY
authors.lastname: Kuang
authors.forename: Yung-Hsiao
authors.initials: YH
authors.lastname: Chiang
authors.forename: Barry
authors.initials: B
authors.lastname: Hoffer
mesh_terms: D000818:Animals; D004298:Dopamine / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism; D004563:Electrochemistry; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D008297:Male; D008694:Methamphetamine / Q000494:pharmacology / Q000633:toxicity*; D051379:Mice; D009154:Mutation; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2 / Q000235:genetics*; D013378:Substantia Nigra / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D050483:Dopamine Plasma Membrane Transport Proteins; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D008694:Methamphetamine; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine