Effects of Subchronic Finasteride Treatment and Withdrawal on Neuroactive Steroid Levels and Their Receptors in the Male Rat Brain

Abstract

The enzymatic conversion of progesterone and testosterone by the enzyme 5alpha-reductase exerts a crucial role in the control of nervous function. The effects of finasteride in the brain, an inhibitor of this enzyme used for the treatment of human benign prostatic hyperplasia and androgenic alopecia, have been poorly explored. Therefore, the effects of a subchronic treatment with finasteride at low doses (3 mg/kg/day) and the consequences of its withdrawal on neuroactive steroid levels in plasma, cerebrospinal fluid and some brain regions as well as on the expression of classical and non-classical steroid receptors have been evaluated in male rats. After subchronic treatment (i.e., for 20 days) the following effects were detected: (i) depending on the compartment considered, alteration in the levels of neuroactive steroids, not only in 5alpha-reduced metabolites but also in its precursors and in neuroactive steroids from other steroidogenic pathways and (ii) an upregulation of the androgen receptor in the cerebral cortex and beta3 subunit of the GABA-A receptor in the cerebellum. One month after the last treatment (i.e., withdrawal period), some of these effects persisted (i.e., the upregulation of the androgen receptor in the cerebral cortex, an increase of dihydroprogesterone in the cerebellum, a decrease of dihydrotestosterone in plasma). Moreover, other changes in neuroactive steroid levels, steroid receptors (i.e., an upregulation of the estrogen receptor alpha and a downregulation of the estrogen receptor beta in the cerebral cortex) and GABA-A receptor subunits (i.e., a decrease of alpha 4 and beta 3 mRNA levels in the cerebral cortex) were detected. These findings suggest that finasteride treatment may have broad consequences for brain function.

Finasteride inhibited brain dopaminergic system and open‐field behaviors in adolescent male rats

“…This result indicated that the administration of finasteride in early developmental stage had no delayed effect on dopaminergic system and exploratory and motor behaviors in late adolescence, because the half‐life period of finasteride is around 6 hours only according to the instruction, and finasteride administrated at early developmental stage had been metabolized before rats developed to adolescent stage. A recent study showed that administration of 3 mg/kg finasteride to young adult rats for 20 days failed to induce changes of dihydrotestosterone level in the cerebral spinal fluid and brain tissue . In the present study, the same dose of finasteride treatment also did not elicit significant change in dopaminergic system or open‐field behaviors in adolescent rats.…”

“…38 In the present study, for adolescent rats, finasteride was initially delivered at postna- A recent study showed that administration of 3 mg/kg finasteride to young adult rats for 20 days failed to induce changes of dihydrotestosterone level in the cerebral spinal fluid and brain tissue. 39 In the present study, the same dose of finasteride treatment also did not elicit significant change in dopaminergic system or open-field behaviors in adolescent rats. Taken together, the present findings that finasteride treatment inhibited dopaminergic system only in adolescent rats rather than early developmental rats suggested that finasteride inhibited dopaminergic system by inhibiting the activity of androgen.…”

“…According to the dose of finasteride used, finasteride group was further divided into 3 subgroups of 3, 25 and 50 mg/kg (n = 7 for each dose). The doses of finasteride were determined based on the previous reports . Rats in finasteride group were repeatedly administrated with finasteride dissolved in sesame oil and ethanol (5% v/v) by subcutaneous injection on the back of rats once a day for 14 days from postnatal day 35‐48.…”

“…The doses of finasteride were determined based on the previous reports. [20][21][22] Rats in finasteride group were repeatedly administrated with finasteride dissolved in sesame oil and ethanol (5% v/v) by subcutaneous injection on the back of rats once a day for 14 days from postnatal day [35][36][37][38][39][40][41][42][43][44][45][46][47][48]. Rats in control group were administrated with vehicle (sesame oil) as the same protocol to those in finasteride group.…”

Adipose tissue dysfunction as a central mechanism leading to dysmetabolic obesity triggered by chronic exposure to p,p’-DDE

“…where dietary supplementation with salmon oil contaminated with a mixture of POPs in conjunction with high-fat (HF) diet feeding promoted the development of obesity and T2D in a rodent model 25, 26 , led to the proposition of a broader metabolism disrupting chemical hypothesis where ECDs act as metabolic disruptors that increase the susceptibility to metabolic diseases 7, 10, 27, 28 . A recent publication reviewed the putative mechanisms of metabolic disruption 28 , highlighting the effects on adipogenesis and adipokine production 29, 30 , neuroendocrine control of feeding and metabolism 31, 32 , energy homeostasis and T2D trough alteration of insulin action, glucose disposal and beta cell survival and function 33 , as well as hepatic steatosis 34 , and hyperlipidemia 35 . Involved molecular mechanism encompass the alteration of hormonal and homeostatic systems related to sex hormones (e.g.…”