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

Schizophrenia Research Institute, Sydney 2021, Australia. .
BMC Neuroscience (Impact Factor: 2.67). 08/2012; 13(1):95. DOI: 10.1186/1471-2202-13-95
Source: PubMed


Increased 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.
We 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.
We 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.

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    • "Gonadal hormones can influence behaviour and brain development via modulation of steroid hormone receptors levels (Juraska et al., 2013), and recent studies have confirmed that testosterone exposure during the peri-pubertal period can alter steroid receptor levels in adulthood (e.g., Nuruddin et al., 2013; Purves-Tyson et al., 2012; Romeo et al., 2000), potentially leading to life-long changes in steroid hormone responsiveness. For example, androgen receptor levels in the hypothalamus were found to be higher in adult male hamsters that had been castrated before puberty than in males that had been castrated post-pubertally (Romeo et al., 2000). "
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    ABSTRACT: Previous research has shown that exposure to testicular hormones during the peri-pubertal period of life has long-term, organizational effects on adult sexual behavior and underlying neural mechanisms in laboratory rodents. However, the organizational effects of peri-pubertal testicular hormones on other aspects of behavior and brain function are less well understood. Here, we investigated the effects of manipulating peri-pubertal testicular hormone exposure on later behavioral responses to novel environments and on hormone receptors in various brain regions that are involved in response to novelty. Male rodents generally spend less time in the exposed areas of novel environments than females, and this sex difference emerges during the peri-pubertal period. Male Lister-hooded rats (Rattus norvegicus) were castrated either before puberty or after puberty, then tested in three novel environments (elevated plus-maze, light-dark box, open field) and in an object/social novelty task in adulthood. Androgen receptor (AR), estrogen receptor (ER1) and corticotropin-releasing factor receptor (CRF-R2) mRNA expression was quantified in the hypothalamus, hippocampus and medial amygdala. The results showed that pre-pubertally castrated males spent more time in the exposed areas of the elevated-plus maze and light-dark box than post-pubertally castrated males, and also confirmed that peri-pubertal hormone exposure influences later response to an opposite-sex conspecific. Hormone receptor gene expression levels did not differ between pre-pubertally and post-pubertally castrated males in any of the brain regions examined. This study therefore demonstrates that testicular hormone exposure during the peri-pubertal period masculinizes later response to novel environments, although the neural mechanisms remain to be fully elucidated. Copyright © 2015. Published by Elsevier Inc.
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    • "This may be particularly pertinent in schizophrenia, as males are more severely impacted (McGrath et al. 2004), and cognitive functions including working memory, processing speed, and verbal memory may be related to testosterone levels in men with schizophrenia (Moore et al. 2013). In male rats, experimental augmentation of testosterone during adolescence (between PND45 and 60) increases dopamine synthesis (Purves-Tyson et al. 2012) and stimulates midbrain expression of DR2 mRNA, dopamine transporter (DAT) mRNA, DAT protein, and vesicular monoamine transporter (VMAT) mRNA at the level of the cell body (Purves-Tyson, under review). This suggests that somatodendritic control of dopamine neurons may be most sensitive to increases in testosterone in adolescent males. "
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    ABSTRACT: Adolescence is a developmental period of complex neurobiological change and heightened vulnerability to psychiatric illness. As a result, understanding factors such as sex and stress hormones which drive brain changes in adolescence, and how these factors may influence key neurotransmitter systems implicated in psychiatric illness, is paramount. In this review, we outline the impact of sex and stress hormones at adolescence on dopamine neurotransmission, a signaling pathway which is critical to healthy brain function and has been implicated in psychiatric illness. We review normative developmental changes in dopamine, sex hormone, and stress hormone signaling during adolescence and throughout postnatal life, then highlight the interaction of sex and stress hormones and review their impacts on dopamine neurotransmission in the adolescent brain. Adolescence is a time of increased responsiveness to sex and stress hormones, during which the maturing dopaminergic neural circuitry is profoundly influenced by these factors. Testosterone, estrogen, and glucocorticoids interact with each other and have distinct, brain region-specific impacts on dopamine neurotransmission in the adolescent brain, shaping brain maturation and cognitive function in adolescence and adulthood. Some effects of stress/sex hormones on cortical and subcortical dopamine parameters bear similarities with dopaminergic abnormalities seen in schizophrenia, suggesting a possible role for sex/stress hormones at adolescence in influencing risk for psychiatric illness via modulation of dopamine neurotransmission. Stress and sex hormones may prove useful targets in future strategies for modifying risk for psychiatric illness.
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    • "Alternatively, the changes in the NE, DA and 5-HT and its metabolites levels in a brain regional-, dose-and age-related manner observed in rats in the present study could be also attributed to a possible amitraz effect on sex steroid hormones that modulate the expression of enzymes such as tyrosine hydroxylase (TH), dopamine-␤-hydroxylase (DBH), tryptophan hydroxylase (TRH), MAO, catechol-O-metyltransferase (COMT), aldehyde dehydrogenase (AD), aldehyde reductase (AR) required for synthesis and metabolism of these neurotransmitters (Donner and Handa, 2009; De Souza Silva et al., 2009; Handa et al., 1997; Lubbers et al., 2010; Luine and Rhodes, 1983; Purves-Tyson et al., 2012; Scardapane and Cardinali, 1977; Thiblin et al., 1999) (Fig. 4). It could be also speculated that amitraz lead to changes of circulating steroid levels and hormonal activity. "
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