title: Testosterone induces molecular changes in dopamine signaling pathway molecules in the adolescent male rat nigrostriatal pathway.
abstract: Adolescent males have an increased risk of developing schizophrenia, implicating testosterone in the precipitation of dopamine-related psychopathology. Evidence from adult rodent brain indicates that testosterone can modulate nigrostriatal dopamine. However, studies are required to understand the role testosterone plays in maturation of dopamine pathways during adolescence and to elucidate the molecular mechanism(s) by which testosterone exerts its effects. We hypothesized that molecular indices of dopamine neurotransmission [synthesis (tyrosine hydroxylase), breakdown (catechol-O-methyl transferase; monoamine oxygenase), transport [vesicular monoamine transporter (VMAT), dopamine transporter (DAT)] and receptors (DRD1-D5)] would be changed by testosterone or its metabolites, dihydrotestosterone and 17β-estradiol, in the nigrostriatal pathway of adolescent male rats. We found that testosterone and dihydrotestosterone increased DAT and VMAT mRNAs in the substantia nigra and that testosterone increased DAT protein at the region of the cell bodies, but not in target regions in the striatum. Dopamine receptor D2 mRNA was increased and D3 mRNA was decreased in substantia nigra and/or striatum by androgens. These data suggest that increased testosterone at adolescence may change dopamine responsivity of the nigrostriatal pathway by modulating, at a molecular level, the capacity of neurons to transport and respond to dopamine. Further, dopamine turnover was increased in the dorsal striatum following gonadectomy and this was prevented by testosterone replacement. Gene expression changes in the dopaminergic cell body region may serve to modulate both dendritic dopamine feedback inhibition and reuptake in the dopaminergic somatodendritic field as well as dopamine release and re-uptake dynamics at the presynaptic terminals in the striatum. These testosterone-induced changes of molecular indices of dopamine neurotransmission in males are primarily androgen receptor-driven events as estradiol had minimal effect. We conclude that nigrostriatal responsivity to dopamine may be modulated by testosterone acting via androgen receptors to alter gene expression of molecules involved in dopamine signaling during adolescence.
authors.affiliation: Schizophrenia Research Institute, Sydney, New South Wales, Australia; Schizophrenia Research Laboratory, Neuroscience Research Australia, Sydney, New South Wales, Australia; School of Medical Sciences, University of New South Wales, Sydney, New South Wales, Australia.
authors.forename: Tertia D
authors.initials: TD
authors.lastname: Purves-Tyson
authors.affiliation: Schizophrenia Research Institute, Sydney, New South Wales, Australia; Schizophrenia Research Laboratory, Neuroscience Research Australia, Sydney, New South Wales, Australia; School of Medical Sciences, University of New South Wales, Sydney, New South Wales, Australia.
authors.forename: Samantha J
authors.initials: SJ
authors.lastname: Owens
authors.affiliation: Discipline of Biomedical Science, School of Medical Sciences, Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Kay L
authors.initials: KL
authors.lastname: Double
authors.affiliation: ANZAC Research Institute, University of Sydney, Concord Hospital, Concord, New South Wales, Australia.
authors.forename: Reena
authors.initials: R
authors.lastname: Desai
authors.affiliation: ANZAC Research Institute, University of Sydney, Concord Hospital, Concord, New South Wales, Australia.
authors.forename: David J
authors.initials: DJ
authors.lastname: Handelsman
authors.affiliation: Schizophrenia Research Institute, Sydney, New South Wales, Australia; Schizophrenia Research Laboratory, Neuroscience Research Australia, Sydney, New South Wales, Australia; School of Psychiatry, University of New South Wales, Sydney, New South Wales, Australia.
authors.forename: Cynthia Shannon
authors.initials: CS
authors.lastname: Weickert
mesh_terms: D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D012739:Gonadal Steroid Hormones / Q000097:blood; D008297:Male; D009919:Orchiectomy; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011954:Receptors, Dopamine / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013378:Substantia Nigra / Q000187:drug effects* / Q000378:metabolism*; D009435:Synaptic Transmission / Q000187:drug effects; D013739:Testosterone / Q000494:pharmacology*
chemical_list: D050483:Dopamine Plasma Membrane Transport Proteins; D012739:Gonadal Steroid Hormones; D012333:RNA, Messenger; D011954:Receptors, Dopamine; D013739:Testosterone; D004298:Dopamine