Previously, we found that testosterone increased TH in the adolescent substantia nigra ; and here, we predicted that activation of sex steroid receptors in male adolescence would lead to increased striatal TH protein and dopamine. Further, dopamine turnover was increased in the dorsal striatum following gonadectomy and this was prevented by testosterone replacement. We detected no change in dopamine concentration in the dorsal striatum at 14 days after gonadectomy but an increase in dopamine turnover in response to gonadectomy – thus, our data may reflect a transitionary phase between 4 and 28 days of replacement. Our evidence indicates that testosterone also increases DRD1 and DRD5 (excitatory receptors) in the substantia nigra and DRD5 in the striatum, suggesting more generalized sensitivity to secreted dopamine via testosterone exposure. In support of the preference for testosterone to induce local changes in molecular indices of dopamine signaling, we find that increases in DAT protein are found proximal to the soma, in the substantia nigra and not distal, in the striatum. However, when comparing gonadectomised and intact rats, changes in dopamine breakdown enzyme or transporter mRNAs or proteins (where measured) were not found in the striatum, thus the changes in dopamine turnover after gonadectomy may reflect post-transcriptional or post-translational changes in the activity of these proteins. We provide data to support our hypothesis that testosterone may modulate, via mainly androgen receptor-driven changes, gene expression of multiple molecules involved in the regulation of dopamine within the nigrostriatal pathway in adolescent male rat brain. Further studies in adult rats suggest other components of dopamine signaling can also be modified by androgens , –. 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. Increased dopamine within the nigrostriatal pathway of patients with schizophrenia is proposed as a driver of psychosis – supported by the effectiveness of antipsychotics (which block dopamine D2 receptors) in diminishing symptoms of hallucinations and delusions . Could acetylcholine be the root of your mental or physical symptoms? However, more research is needed to fully understand how testosterone impacts Alzheimer’s disease progression. Testosterone levels have been observed to decrease with age, which can contribute to the decline in cognitive functions. However, it also plays a significant role in brain function. Let’s explore how these elements interact and their implications for brain function. (D) DRD2 short mRNA was increased relative to the Intact group by testosterone and DHT replacement but not by17β-estradiol replacement. (C) DRD2 pan mRNA was increased by testosterone, DHT and 17β-estradiol replacement relative to the Intact group. (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. (C) DRD2 pan, (D) DRD2 short and (E) DRD2 long mRNAs were increased by testosterone and DHT replacement relative to Intact and Gdx groups. DAT (A) and VMAT (B) mRNA expression were increased by androgens but not by 17β-estradiol replacement. Comparisons of DAT protein levels were made using one-directional t tests (GraphPad Prism) due to an a priori hypothesis , based on mRNA findings, that DAT protein would be increased by androgens relative to the Intact and Gdx groups. In the current work, we tested the hypothesis that testosterone can induce androgen receptor-driven changes in gene expression of multiple molecules involved in the regulation of dopamine neurotransmission in the nigrostriatal pathway in adolescent male rat brain. For example, in several species of mammals and birds, the distribution of the neuropeptide hormones arginine vasotocin (AVT) and arginine vasopressin (AVP) in the pre-optic and septal regions of the brain differs between the sexes. Furthermore, hormones other than testosterone and its derivatives also may be involved in the modulation of aggression. In addition, testosterone of nongonadal origin (i.e., produced by the adrenal gland) may be important in aggression outside the breeding season, as in the case of birds such as the song sparrow that maintain nonbreeding territories in the winter. For instance, the more elaborate the social structure of a species, the less drastic are the effects of castration on aggression. The close link between aggression and testosterone is not surprising, given that males of many species fight over access to fertile females, but the connection is complex. In male mice the scent of another male’s urine, which contains the breakdown products of testosterone, elicits intense aggressive responses. Castration has been found to reduce aggression dramatically, while experimental reinstatement of testosterone—for instance, through injection into the blood—restores aggression. DRD2 pan mRNA was increased by T, DHT and E relative to the Intact group (Fig. 2C). Testosterone and 17β- estradiol replacement had no effect on DRD1 mRNA expression. (F) DRD3 mRNA was decreased by testosterone and DHT replacement relative to Gdx. 17β-estradiol replacement had no effect on DRD2pan, D2S or D2L mRNA levels. VMAT mRNA was increased 26% and 35% by T and DHT, respectively, when compared to the Gdx group and 27% and 36% by T and DHT, respectively, when compared to the Intact group. DAT mRNA was increased 40% and 50% by T and DHT, respectively, when compared to the Gdx group and 45% and 54% by T and DHT, respectively, when compared to the Intact group. Samples were run alongside a seven-point standard curve using serial dilutions of cDNA derived from SN or striatum RNA pooled from a subset of 25 rats (taken from all treatment groups). Male Sprague-Dawley rats experience an increase in circulating testosterone between 45 and 60 days of age – and at 60 days of age are considered young adults. Male rats were gonadectomised at 45 days of age and given continuous replacement testosterone (T), DHT or 17β-estradiol (E) by subdermal silastic implant – for two weeks. Evidence regarding the mechanism(s) by which testosterone modulates nigrostriatal dopamine neurotransmission in the adult mammalian brain is, however, conflicting –. In order for testosterone to change gene expression, it can bind directly to the transcription factors, androgen receptor (AR) or, following conversion to estradiol by aromatase, to estrogen receptors (ERα, ERβ).
