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

Li, Li; Kang, Yunxiao; Ji, Xiaoming; Li, Yingkun; Li, Shuangcheng; Zhang, Xiangjian; Cui, Huixian; Shi, Geming

doi:10.1111/cns.12781

Cited by 23 publications

(9 citation statements)

References 54 publications

(108 reference statements)

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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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Section: Androgens Regulate Executive Functionmentioning

confidence: 69%

Androgen Regulation of the Mesocorticolimbic System and Executive Function

et al. 2018

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“…Immobility in TST may assess the strength and energy of the movement of mice, a sign of reluctance to maintain effort [ 66 , 67 ], while as previously reported, activity in OFT can reflect neurotransmitter system effects on stimulus salience and behavioral activity [ 68 , 69 ], suggesting a key role of ENZ on motivation to explore. Interestingly, pharmacological inhibition of T conversion to DHT in non-castrated adolescent rats affected exploratory and motor behaviors in OFT by down-regulating dopaminergic activity in SNpc and VTA [ 70 ]. These behavioral observations were strengthened by the expression of androgen components [ 50 ] within the nigrostriatal circuitry in TH+-structures.…”

Section: Discussionmentioning

confidence: 99%

The Prostate Cancer Therapy Enzalutamide Compared with Abiraterone Acetate/Prednisone Impacts Motivation for Exploration, Spatial Learning and Alters Dopaminergic Transmission in Aged Castrated Mice

Nicola

Dubois

Campart

et al. 2021

Cancers

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Cognitive side effects after cancer treatment threatening quality of life (QoL) constitute a major challenge in oncology. Abiraterone acetate plus prednisone (AAP) and enzalutamide (ENZ) are examples of next-generation therapy (NGT) administered to metastatic castration-resistant prostate cancer (mCRPC) patients. NGT significantly improved mCRPC overall survival but neurological side effects such as fatigue and cognitive impairment were reported. We developed a behavioral 17 months-aged and castrated mouse model receiving per os AAP or ENZ for 5 days per week for six consecutive weeks. ENZ exposure reduced spontaneous activity and exploratory behavior associated with a decreased tyrosine hydroxylase (TH)-dopaminergic activity in the substantia nigra pars compacta and the ventral tegmental area. A decrease in TH+-DA afferent fibers and Phospho-DARPP32-related dopaminergic neuronal activities in the striatum and the ventral hippocampus highlighted ENZ-induced dopaminergic regulation within the nigrostriatal and mesolimbocortical pathways. ENZ and AAP treatments did not substantially modify spatial learning and memory performances, but ENZ led to a thygmotaxis behavior impacting the cognitive score, and reduced c-fos-related activity of NeuN+-neurons in the dorsal hippocampus. The consequences of the mCRPC treatment ENZ on aged castrated mouse motivation to exploration and cognition should make reconsider management strategy of elderly prostate cancer patients.

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“…58 Preclinical studies have demonstrated that treating rodents with finasteride increases depressive and anxiety phenotypes. 59,60 Despite the patient outcry, 58 accumulating evidence (for review, see Alhetheli et al, 50 Hirshburg et al, 51 and Traish 52 ), and high potential cost to benefit of the use of these compounds, there remain skeptics and advocates for their continued use 61 when in fact this is a significant issue for patients and a "surmountable challenge for clinicians". 52 Consistent with these clinical findings, preclinical studies demonstrate that finasteride treatment alters valence processing.…”

Section: Endogenous Neurosteroids and Affective Tonementioning

confidence: 99%

Witnessed trauma exposure induces fear in mice through a reduction in endogenous neurosteroid synthesis

Evans‐Strong,

Walton,

Blandino

et al. 2024

J Neuroendocrinology

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Neurosteroids have been implicated in the pathophysiology of post‐traumatic stress disorder (PTSD). Allopregnanolone is reduced in subsets of individuals with PTSD and has been explored as a novel treatment strategy. Both direct trauma exposure and witnessed trauma are risk factors for PTSD; however, the role of neurosteroids in the behavioral outcomes of these unique experiences has not been explored. Here, we investigate whether observational fear is associated with a reduced capacity for endogenous neurosteroidogenesis and the relationship with behavioral outcomes. We demonstrated that mice directly subjected to a threat (foot shocks) and those witnessing the threat have decreased plasma levels of allopregnanolone. The expression of a key enzyme involved in endogenous neurosteroid synthesis, 5α‐reductase type 2, is decreased in the basolateral amygdala, which is a major emotional processing hub implicated in PTSD. We demonstrated that genetic knockdown or pharmacological inhibition of 5α‐reductase type 2 exaggerates the behavioral expression of fear in response to witnessed trauma, whereas oral treatment with an exogenous, synthetic neuroactive steroid gamma‐aminobutyric acid‐A receptor positive allosteric modulator with molecular pharmacology similar to allopregnanolone (SGE‐516 [tool compound]) decreased the behavioral response to observational fear. These data implicate impaired endogenous neurosteroidogenesis in the pathophysiology of threat exposure, both direct and witnessed. Further, these data suggest that treatment with exogenous 5α‐reduced neurosteroids or targeting endogenous neurosteroidogenesis may be beneficial for the treatment of individuals with PTSD, whether resulting from direct or witnessed trauma.

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

Cited by 23 publications

References 54 publications

Androgen Regulation of the Mesocorticolimbic System and Executive Function

Androgen Regulation of the Mesocorticolimbic System and Executive Function

The Prostate Cancer Therapy Enzalutamide Compared with Abiraterone Acetate/Prednisone Impacts Motivation for Exploration, Spatial Learning and Alters Dopaminergic Transmission in Aged Castrated Mice

Witnessed trauma exposure induces fear in mice through a reduction in endogenous neurosteroid synthesis

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