Testosterone regulation of sex steroid-related mRNAs and dopamine-related mRNAs in adolescent male rat substantia nigra

Abstract

BackgroundIncreased risk of schizophrenia in adolescent males indicates that a link between the development of dopamine-related psychopathology and testosterone-driven brain changes may exist. However, contradictions as to whether testosterone increases or decreases dopamine neurotransmission are found and most studies address this in adult animals. Testosterone-dependent actions in neurons are direct via activation of androgen receptors (AR) or indirect by conversion to 17β-estradiol and activation of estrogen receptors (ER). How midbrain dopamine neurons respond to sex steroids depends on the presence of sex steroid receptor(s) and the level of steroid conversion enzymes (aromatase and 5α-reductase). We investigated whether gonadectomy and sex steroid replacement could influence dopamine levels by changing tyrosine hydroxylase (TH) protein and mRNA and/or dopamine breakdown enzyme mRNA levels [catechol-O-methyl transferase (COMT) and monoamine oxygenase (MAO) A and B] in the adolescent male rat substantia nigra. We hypothesized that adolescent testosterone would regulate sex steroid signaling through regulation of ER and AR mRNAs and through modulation of aromatase and 5α-reductase mRNA levels.ResultsWe find ERα and AR in midbrain dopamine neurons in adolescent male rats, indicating that dopamine neurons are poised to respond to circulating sex steroids. We report that androgens (T and DHT) increase TH protein and increase COMT, MAOA and MAOB mRNAs in the adolescent male rat substantia nigra. We report that all three sex steroids increase AR mRNA. Differential action on ER pathways, with ERα mRNA down-regulation and ERβ mRNA up-regulation by testosterone was found. 5α reductase-1 mRNA was increased by AR activation, and aromatase mRNA was decreased by gonadectomy.ConclusionsWe conclude that increased testosterone at adolescence can shift the balance of sex steroid signaling to favor androgenic responses through promoting conversion of T to DHT and increasing AR mRNA. Further, testosterone may increase local dopamine synthesis and metabolism, thereby changing dopamine regulation within the substantia nigra. We show that testosterone action through both AR and ERs modulates synthesis of sex steroid receptor by altering AR and ER mRNA levels in normal adolescent male substantia nigra. Increased sex steroids in the brain at adolescence may alter substantia nigra dopamine pathways, increasing vulnerability for the development of psychopathology.

Testosterone and reward prediction-errors in healthy men and men with schizophrenia

“…The relationship with testosterone in the healthy men is consistent with the sex steroid modulation of reward prediction-error signals in the ventral striatum and may reflect changes in dopamine signaling. We also detected testosterone receptors (AR) in the human midbrain consistent with the direct modulation of dopamine by sex steroids and thus, dopamine neurons could be mediators of the testosterone-related changes we observed in the ventral striatum BOLD signal which is also supported by findings of testosterone directly regulating dopamine related gene expression in male rodents (Purves-Tyson et al, 2012). In addition, in post mortem human male substantia nigra we showed that tyrosine hydroxylase gene expression, an indicator of dopamine synthesis capacity, was positively (B) regions of a significant two-way interaction between group, i.e., HM N men with schizophrenia (SZ), neural activity and testosterone levels in the striatum; (C) the significant correlation between the BOLD parameter estimates (UR N ER) and testosterone at the peak voxel in HM; and (D) the negative (and non-significant) correlation between BOLD parameter estimates (UR N ER) and testosterone in SZ, confirming the significant two-way interaction in B was due to a weaker or reversed effect among SZ.…”

“…In particular, we have found that circulating testosterone levels in adolescent male rhesus macaques correlate with dopamine synthesis potential, as inferred from increased striatal tyrosine hydroxylase levels -the rate-limiting step in dopamine biosynthesis (Morris et al, 2010). Our studies in rodents also find that testosterone triggers a positive feedback loop to change the level of dopamine receptors and breakdown enzymes and dopamine transporters via AR action (Purves-Tyson et al, 2012. Our current study of human post mortem substantia nigra in patients and controls also found a positive association between a potential functional expression of AR and tyrosine hydroxylase.…”

“…Testosterone can bind to androgen receptors (AR) and after conversion by aromatase to estradiol, to estrogen receptors (ERα and ERβ). In rodents, most studies demonstrate that dopamine neurons express AR and both estrogen receptors (Shughrue et al, 1997;Perez et al, 2003;de Souza Silva et al, 2009;Purves-Tyson et al, 2012). Evidence from conditioned place preference studies in rodents (de Beun et al, 1992;Alexander et al, 1994) and anabolic steroid addiction in human males (Kanayama et al, 2009(Kanayama et al, , 2010 suggest testosterone can act as a positive reinforcer.…”

Early antipsychotic treatment in childhood/adolescent period has long-term effects on depressive-like, anxiety-like and locomotor behaviours in adult rats

“…During adolescence, testosterone and estrogen influence brain maturation/development in dopaminergic regions including the striatum and prefrontal cortex, and also have a significant role in shaping the dopaminergic signal (Andersen 2003;Purves-Tyson et al 2012;Sinclair et al 2014).…”

Testosterone attenuates and the selective estrogen receptor modulator, raloxifene, potentiates amphetamine-induced locomotion in male rats

“…We reported that increasing testosterone over the male adolescent period (postnatal day [PND] 45-60) resulted in an increase in dopamine synthesis potential (tyrosine hydroxylase [TH] protein expression) in the young adult substantia nigra (Purves-Tyson et al, 2012) but not in the striatum (Purves-Tyson et al, 2014), but also found in late adolescent rhesus macaques that circulating testosterone levels correlated with TH levels in the putamen (Morris et al, 2010). We also reported, in young adult rats, that increasing testosterone over the adolescent period increased dopamine receptor D2 (DRD2) gene expression in both the substantia nigra and dorsal striatum (Purves-Tyson et al, 2014).…”