Exploring the neural mechanisms of finasteride: a proteomic analysis in the nucleus accumbens

Soggiu, Alessio; Piras, Cristian; Greco, Viviana; Devoto, Paola; Urbani, Andrea; Calzetta, Luigino; Bortolato, Marco; Roncada, Paola

doi:10.1016/j.psyneuen.2016.10.001

Cited by 14 publications

(8 citation statements)

References 79 publications

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“…In addition to the reduction in HPA axis hormones, other mechanisms may be involved in the effects of FIN. For example, the effects of this drug on the reduction of responses to salient stimuli may reflect the marked antidopaminergic effects of FIN in the prefrontal cortex and nucleus accumbens, which have been documented by our previous studies [26,61,62,63]; indeed, dopaminergic signaling in these brain areas is pivotal to allowing for behavioral arousal and salience appraisal [64,65]. Future studies are needed to understand the involvement of the HPA axis, dopamine pathways, or other neural mechanisms in the behavioral effects of FIN.…”

Section: Discussionmentioning

confidence: 78%

The Steroidogenesis Inhibitor Finasteride Reduces the Response to Both Stressful and Rewarding Stimuli

et al. 2019

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Finasteride (FIN) is the prototypical inhibitor of steroid 5α-reductase (5αR), the enzyme that catalyzes the rate-limiting step of the conversion of progesterone and testosterone into their main neuroactive metabolites. FIN is clinically approved for the treatment of benign prostatic hyperplasia and male baldness; while often well-tolerated, FIN has also been shown to cause or exacerbate psychological problems in vulnerable subjects. Evidence on the psychological effects of FIN, however, remains controversial, in view of inconsistent clinical reports. Here, we tested the effects of FIN in a battery of tests aimed at capturing complementary aspects of mood regulation and stress reactivity in rats. FIN reduced exploratory, incentive, prosocial, and risk-taking behavior; furthermore, it decreased stress coping, as revealed by increased immobility in the forced-swim test (FST). This last effect was also observed in female and orchiectomized male rats, suggesting that the mechanism of action of FIN does not primarily reflect changes in gonadal steroids. The effects of FIN on FST responses were associated with a dramatic decrease in corticotropin release hormone (CRH) mRNA and adrenocorticotropic hormone (ACTH) levels. These results suggest that FIN impairs stress reactivity and reduces behavioral activation and impulsive behavior by altering the function of the hypothalamus–pituitary–adrenal (HPA) axis.

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Section: Discussionmentioning

confidence: 78%

The Steroidogenesis Inhibitor Finasteride Reduces the Response to Both Stressful and Rewarding Stimuli

et al. 2019

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“…the Cyp17a1 inhibitor abiraterone. Along with studies using systemic finasteride [5αR inhibitor ( 163 , 164 , 222 , 223 )], these results suggest that local androgen synthesis regulates DA signaling in the mesocorticolimbic system and DA-dependent behaviors. While these studies are informative, there still remains an important gap in our understanding of how neural androgen production specifically influences executive functioning.…”

Section: Androgens Regulate Executive Functionmentioning

confidence: 69%

Androgen Regulation of the Mesocorticolimbic System and Executive Function

et al. 2018

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Multiple lines of evidence indicate that androgens, such as testosterone, modulate the mesocorticolimbic system and executive function. This review integrates neuroanatomical, molecular biological, neurochemical, and behavioral studies to highlight how endogenous and exogenous androgens alter behaviors, such as behavioral flexibility, decision making, and risk taking. First, we briefly review the neuroanatomy of the mesocorticolimbic system, which mediates executive function, with a focus on the ventral tegmental area (VTA), nucleus accumbens (NAc), medial prefrontal cortex (mPFC), and orbitofrontal cortex (OFC). Second, we present evidence that androgen receptors (AR) and other steroid receptors are expressed in the mesocorticolimbic system. Using sensitive immunohistochemistry and quantitative polymerase chain reaction (qPCR) techniques, ARs are detected in the VTA, NAc, mPFC, and OFC. Third, we describe recent evidence for local androgens (“neuroandrogens”) in the mesocorticolimbic system. Steroidogenic enzymes are expressed in mesocorticolimbic regions. Furthermore, following long-term gonadectomy, testosterone is nondetectable in the blood but detectable in the mesocorticolimbic system, using liquid chromatography tandem mass spectrometry. However, the physiological relevance of neuroandrogens remains unknown. Fourth, we review how anabolic-androgenic steroids (AAS) influence the mesocorticolimbic system. Fifth, we describe how androgens modulate the neurochemistry and structure of the mesocorticolimbic system, particularly with regard to dopaminergic signaling. Finally, we discuss evidence that androgens influence executive functions, including the effects of androgen deprivation therapy and AAS. Taken together, the evidence indicates that androgens are critical modulators of executive function. Similar to dopamine signaling, there might be optimal levels of androgen signaling within the mesocorticolimbic system for executive functioning. Future studies should examine the regulation and functions of neurosteroids in the mesocorticolimbic system, as well as the potential deleterious and enduring effects of AAS use.

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“…These analyses may prove essential to help clarify the male predominance of TS, as well as potential mechanisms of comorbidity with other neuropsychiatric problems, including ADHD and OCD. Fourth, our analyses were only limited to the PFC of adult mice; however, it is likely that the effects of other neurosteroids may differ with age; furthermore, other regions, such as the nucleus accumbens, may be involved in the effects of finasteride 47 . Given the limitations in the size of this region, however, further improvements in our ability to detect neurosteroid levels will be needed to address this issue.…”

Section: Discussionmentioning

confidence: 99%

Allopregnanolone mediates the exacerbation of Tourette-like responses by acute stress in mouse models

Mosher

Godar

Nelson

et al. 2017

Sci Rep

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Tourette syndrome (TS) is a neuropsychiatric disorder characterized by multiple tics and sensorimotor abnormalities, the severity of which is typically increased by stress. The neurobiological underpinnings of this exacerbation, however, remain elusive. We recently reported that spatial confinement (SC), a moderate environmental stressor, increases tic-like responses and elicits TS-like sensorimotor gating deficits in the D1CT-7 mouse, one of the best-validated models of TS. Here, we hypothesized that these adverse effects may be mediated by neurosteroids, given their well-documented role in stress-response orchestration. Indeed, SC increased the levels of progesterone, as well as its derivatives 5α-dihydroprogesterone and allopregnanolone, in the prefrontal cortex (PFC) of D1CT-7 mice. Among these steroids, however, only allopregnanolone (5–15 mg/kg, IP) dose-dependently exacerbated TS-like manifestations in D1CT-7, but not wild-type littermates; these effects were countered by the benchmark anti-tic therapy haloperidol (0.3 mg/kg, IP). Furthermore, the phenotypic effects of spatial confinement in D1CT-7 mice were suppressed by finasteride (25–50 mg/kg, IP), an inhibitor of the main rate-limiting enzyme in allopregnanolone synthesis. These findings collectively suggest that stress may exacerbate TS symptoms by promoting allopregnanolone synthesis in the PFC, and corroborate previous clinical results pointing to finasteride as a novel therapeutic avenue to curb symptom fluctuations in TS.

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Exploring the neural mechanisms of finasteride: a proteomic analysis in the nucleus accumbens

Cited by 14 publications

References 79 publications

The Steroidogenesis Inhibitor Finasteride Reduces the Response to Both Stressful and Rewarding Stimuli

The Steroidogenesis Inhibitor Finasteride Reduces the Response to Both Stressful and Rewarding Stimuli

Androgen Regulation of the Mesocorticolimbic System and Executive Function

Allopregnanolone mediates the exacerbation of Tourette-like responses by acute stress in mouse models

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