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Cited by 109Neurotransmitter Receptor Influence on BehaviorSchizophrenia research and treatmentNeuroscience and Neuropharmacology Research

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Testosterone Induces Molecular Changes in Dopamine Signaling Pathway Molecules in the Adolescent Male Rat Nigrostriatal Pathway

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Purves-Tyson, Tertia D., Owens, Samantha J., Double, Kay L., Desai, Reena, Handelsman, David J., Weickert, Cynthia Shannon·2014·PLoS ONE
DOI 10.1371/journal.pone.0091151PMC PMC3949980
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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.

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Figure 1 Effect of gonadectomy and sex steroid replacement on presynaptic dopamine transporter and dopamine receptor mRNA expression in the substantia nigra of adolescent male rats. DAT (A) and VMAT (B) mRNA expression were increased by androgens but not by 17β-estradiol replacement. (C) DRD2 pan, (D) DRD2 short and (E) DRD2 long mRNAs were increased by testosterone and DHT replacement relative to Intact and Gdx groups. 17β-estradiol replacement had no effect on DRD2pan, D2S or D2L mRNA levels. (F) DRD3 mRNA was decreased by testosterone and DHT replacement relative to Gdx. 17β-estradiol replacement had no effect on DRD3 mRNA. (G) DRD1 mRNA was increased by DHT replacement relative to Gdx. Testosterone and 17β- estradiol replacement had no effect on DRD1 mRNA expression. (H) DRD5 mRNA was increased by testosterone replacement relative to Intact and Gdx groups and increased by DHT and 17β-estradiol replacement relative to the Gdx group. * denotes comparison with Intact, unless comparison is indicated by a line, # denotes comparison with the Gdx group, * and # p<0.05, ** and ## p<0.01, *** and ### p<0.001, n = 12–15/group.
Figure 1 Effect of gonadectomy and sex steroid replacement on presynaptic dopamine transporter and dopamine receptor mRNA expression in the substantia nigra of adolescent male rats. DAT (A) and VMAT (B) mRNA expression were increased by androgens but not by 17β-estradiol replacement. (C) DRD2 pan, (D) DRD2 short and (E) DRD2 long mRNAs were increased by testosterone and DHT replacement relative to Intact and Gdx groups. 17β-estradiol replacement had no effect on DRD2pan, D2S or D2L mRNA levels. (F) DRD3 mRNA was decreased by testosterone and DHT replacement relative to Gdx. 17β-estradiol replacement had no effect on DRD3 mRNA. (G) DRD1 mRNA was increased by DHT replacement relative to Gdx. Testosterone and 17β- estradiol replacement had no effect on DRD1 mRNA expression. (H) DRD5 mRNA was increased by testosterone replacement relative to Intact and Gdx groups and increased by DHT and 17β-estradiol replacement relative to the Gdx group. * denotes comparison with Intact, unless comparison is indicated by a line, # denotes comparison with the Gdx group, * and # p<0.05, ** and ## p<0.01, *** and ### p<0.001, n = 12–15/group.CC BY · PubMed Central
Figure 2 Effect of gonadectomy and sex steroid replacement on dopamine metabolic enzyme and dopamine receptor mRNA expression in the dorsal striatum of adolescent male rats. There was no effect of treatment group on mRNA expression of COMT (A) or MAOA (B). (C) DRD2 pan mRNA was increased by testosterone, DHT and 17β-estradiol replacement relative to the Intact group. (D) DRD2 short mRNA was increased relative to the Intact group by testosterone and DHT replacement but not by17β-estradiol replacement. (E) There was a trend for treatment group to change DRD2 long mRNA expression (F = 2.36, df = (4,65), p = 0.063). There were no statistically significant sex steroid-related changes in (F) DRD3 mRNA (F = 1.62, df = (4,65), p = 0.18) or (G) DRD1 mRNA (F = 2.10, df = (4,65), p = 0.015) (H) DRD5 mRNA expression was increased relative to the Intact group by Gdx, testosterone and DHT replacement but not by 17β-estradiol replacement. * denotes comparison with intact, * p<0.05, ** p<0.01, n = 12–16/group.
Figure 2 Effect of gonadectomy and sex steroid replacement on dopamine metabolic enzyme and dopamine receptor mRNA expression in the dorsal striatum of adolescent male rats. There was no effect of treatment group on mRNA expression of COMT (A) or MAOA (B). (C) DRD2 pan mRNA was increased by testosterone, DHT and 17β-estradiol replacement relative to the Intact group. (D) DRD2 short mRNA was increased relative to the Intact group by testosterone and DHT replacement but not by17β-estradiol replacement. (E) There was a trend for treatment group to change DRD2 long mRNA expression (F = 2.36, df = (4,65), p = 0.063). There were no statistically significant sex steroid-related changes in (F) DRD3 mRNA (F = 1.62, df = (4,65), p = 0.18) or (G) DRD1 mRNA (F = 2.10, df = (4,65), p = 0.015) (H) DRD5 mRNA expression was increased relative to the Intact group by Gdx, testosterone and DHT replacement but not by 17β-estradiol replacement. * denotes comparison with intact, * p<0.05, ** p<0.01, n = 12–16/group.CC BY · PubMed Central
Figure 3 Effect of gonadectomy and sex steroid replacement on dopamine transporter protein in the substantia nigra of adolescent male rats. In the substantia nigra there was a trend for treatment group to change DAT protein (F = 2.52, df = (4,41), p = 0.056). Representative immunoblots of a subset of substantia nigra samples show DAT (50 kDa) and β-actin (43 kDa). A priori, planned comparisons, based on mRNA data, revealed that testosterone replacement increased DAT protein compared to the gonadectomised group. * p<0.05, n = 9–10/group. (MWM, molecular weight marker; std, internal standard).
Figure 3 Effect of gonadectomy and sex steroid replacement on dopamine transporter protein in the substantia nigra of adolescent male rats. In the substantia nigra there was a trend for treatment group to change DAT protein (F = 2.52, df = (4,41), p = 0.056). Representative immunoblots of a subset of substantia nigra samples show DAT (50 kDa) and β-actin (43 kDa). A priori, planned comparisons, based on mRNA data, revealed that testosterone replacement increased DAT protein compared to the gonadectomised group. * p<0.05, n = 9–10/group. (MWM, molecular weight marker; std, internal standard).CC BY · PubMed Central
Figure 4 Effect of gonadectomy and sex steroid replacement on dopamine transporter protein and tyrosine hydroxylase protein in adolescent male rat dorsal striatum. (A) DAT protein was unchanged in the dorsal striatum by gonadectomy and sex steroid replacement (F = 2.39, df = (4,45), p = 0.07). Representative immunoblots of a subset of dorsal striatum samples from all five groups show DAT (50 kDa) and β-actin (43 kDa). (B) TH protein was unchanged by gonadectomy or sex steroid replacement in the dorsal striatum (F = 0.41, df = (4,45), p = 0.78). Representative immunoblots of a subset of dorsal striatum samples from all five groups show TH protein (60 kDa) and β-actin protein (43 kDa). * p<0.05, n = 9–10/group. (MWM, molecular weight marker; std, internal standard).
Figure 4 Effect of gonadectomy and sex steroid replacement on dopamine transporter protein and tyrosine hydroxylase protein in adolescent male rat dorsal striatum. (A) DAT protein was unchanged in the dorsal striatum by gonadectomy and sex steroid replacement (F = 2.39, df = (4,45), p = 0.07). Representative immunoblots of a subset of dorsal striatum samples from all five groups show DAT (50 kDa) and β-actin (43 kDa). (B) TH protein was unchanged by gonadectomy or sex steroid replacement in the dorsal striatum (F = 0.41, df = (4,45), p = 0.78). Representative immunoblots of a subset of dorsal striatum samples from all five groups show TH protein (60 kDa) and β-actin protein (43 kDa). * p<0.05, n = 9–10/group. (MWM, molecular weight marker; std, internal standard).CC BY · PubMed Central
Figure 5 The effect of gonadectomy and sex steroid replacement on dopamine, dopamine metabolites and dopamine turnover in the dorsal striatum of adolescent male rats. There was no significant effect of treatment group on dopamine (A) or HVA (C). Gonadectomy increased DOPAC (B) and this increase was attenuated by testosterone replacement only. Dopamine turnover (D) was significantly increased by gonadectomy and this was attenuated by testosterone and DHT replacement but not 17β-estradiol replacement. * denotes comparison with Intact unless comparison indicated by a line, # denotes comparison with the Gdx group, * and # p<0.05; ** and ## p<0.01, n = 11–16/group for all.
Figure 5 The effect of gonadectomy and sex steroid replacement on dopamine, dopamine metabolites and dopamine turnover in the dorsal striatum of adolescent male rats. There was no significant effect of treatment group on dopamine (A) or HVA (C). Gonadectomy increased DOPAC (B) and this increase was attenuated by testosterone replacement only. Dopamine turnover (D) was significantly increased by gonadectomy and this was attenuated by testosterone and DHT replacement but not 17β-estradiol replacement. * denotes comparison with Intact unless comparison indicated by a line, # denotes comparison with the Gdx group, * and # p<0.05; ** and ## p<0.01, n = 11–16/group for all.CC BY · PubMed Central

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Metadata

Authors
Purves-Tyson, T. D., Owens, S. J., Double, K. L., Desai, R., Handelsman, D. J., & Weickert, C. S.
Affiliations
  • UNSW Sydney (AU)
  • The University of Sydney (AU)
Corresponding author
  • Purves-Tyson, Tertia D.
  • Owens, Samantha J.
  • Double, Kay L.
  • Desai, Reena
  • Handelsman, David J.
  • Weickert, Cynthia Shannon
ORCID
Venue
PLoS ONE
Publisher
Public Library of Science (PLoS)
Published
2014-03-11
Volume
9
Issue
3
Pages
e91151
ISSN
1932-6203 (ISSN-L)
DOI
10.1371/journal.pone.0091151
PMC
PMC3949980
OpenAlex
W2003231418
Cited by
109
References
66
Citations by year
2026: 9 · 2025: 8 · 2024: 7 · 2023: 11 · 2022: 6 · 2021: 7 · 2020: 11 · 2019: 13 · 2018: 9 · 2017: 12 · 2016: 7 · 2015: 5 · 2014: 4
FWCI
4.26
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS ONE (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, other-oa)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • UNSWorks (UNSW Sydney) (submittedVersion, cc-by-nc-nd)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Neuroscience Research Australia
  • University of New South Wales
  • NSW Ministry of Health
  • Macquarie Group Foundation
  • Medical Research Council
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
  • Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords
testosterone, dopamine signaling, nigrostriatal pathway, adolescence, dopamine transporter, vesicular monoamine transporter, dopamine receptors, dopamine D2 receptor, dopamine D3 receptor, dihydrotestosterone, estradiol, androgen receptor, substantia nigra, dorsal striatum, dopamine turnover, schizophrenia risk, gonadectomy, gene expression
MeSH terms
Animals, Corpus Striatum, Dopamine, Gene Expression Regulation, Male, Synaptic Transmission, Orchiectomy, Receptors, Dopamine, RNA, Messenger, Gonadal Steroid Hormones, Substantia Nigra, Testosterone, Signal Transduction, Dopamine Plasma Membrane Transport Proteins, Rats

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