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.
Highlights
Schizophrenia is slightly more common in males than females [1]
Gonadectomy reduced tyrosine hydroxylase (TH) activity in the striatum of adult male rats and this reduction was prevented by testosterone [23].We recently reported that testosterone increased catechol-O-methyl transferase (COMT) and MAO mRNAs in the adolescent male rat substantia nigra (SN), implying increased dopamine turnover capacity in the nigrostriatal pathway in male adolescence [16]
We found a significant effect of treatment group on DRD2 pan mRNA (F = 8.5, df = (4,65), p, 0.0001) (Fig. 1C)
Summary
The peak age of onset of schizophrenia in males is concomitant with higher testosterone levels at adolescence and young adulthood, suggesting testosterone may be linked to the onset of psychosis in vulnerable individuals [2]. Imaging studies provide direct evidence of dysregulation of striatal dopamine transmission in schizophrenia underlying the development of psychosis [7,8] but the underlying molecular cause(s) of this dopamine dysregulation are unknown. Understanding the molecular mechanisms by which testosterone modulates the maturation and regulation of nigrostriatal dopamine responsivity during adolescence is crucial to understanding the possible role of testosterone in schizophrenia risk. Dopaminergic transmission involves signaling by five G-protein coupled receptors divided into inhibitory receptors (DRD2, DRD3, DRD4) and excitatory receptors (DRD1, DRD5), as well as the regulation of dopamine movement across membranes via dopamine transporter (DAT) and vesicular monoamine transporter (VMAT2). Dopamine homeostasis is maintained by dopamine biosynthesis, transport and breakdown, all potentially modulated by testosterone-induced changes in gene expression and/or protein levels of the molecules involved
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
