Androgen synthesis inhibition increases behavioural flexibility and mPFC tyrosine hydroxylase in gonadectomized male rats

Abstract

Behavioural flexibility is essential to adapt to a changing environment and depends on the medial prefrontal cortex (mPFC). Testosterone administration decreases behavioural flexibility. It is well known that testosterone is produced in the gonads, but testosterone is also produced in the brain, including the mPFC and other nodes of the mesocorticolimbic system. It is unclear how testosterone produced in the brain versus the gonads influences behavioural flexibility. Here, in adult male rats, we assessed the effects of the androgen synthesis inhibitor abiraterone acetate (ABI) and long-term gonadectomy (GDX) on behavioural flexibility in two paradigms. In Experiment 1, ABI but not GDX reduced the number of errors to criterion and perseverative errors in a strategy set-shifting task. In Experiment 2, with a separate cohort of rats, ABI but not GDX reduced perseverative errors in a reversal learning task. In Experiment 1, we also examined tyrosine hydroxylase immunoreactivity (TH-ir), and ABI but not GDX increased TH-ir in the mPFC. Our findings suggest that neurally-produced androgens modulate behavioural flexibility via modification of dopamine signalling in the mesocorticolimbic system. These results indicate that neurosteroids regulate executive functions and that ABI treatment for prostate cancer might affect cognition.

Sex differences in cognitive flexibility are driven by the estrous cycle and stress-dependent

“…However, more direct measurements of estrogen levels would be beneficial for more straightforward investigations of the effects of estrogen on task performances. In addition, as testosterone has been also shown to impact performance in cognitive flexibility tasks (Wallin and Wood, 2015 ; Tomm et al, 2022 ), and testosterone levels can vary by individuals (Viau, 2002 ), measurements or experimental designs with testosterone could add more insights into the understanding of sex differences in cognitive flexibility (Shansky, 2019 ).…”

“…Indeed, understanding the neural circuits of cognitive flexibility would provide more clarity as to how sex differences in behavior are mediated. Previous research has indicated the importance of dopaminergic input on cognitive flexibility (Floresco et al, 2008 ; Haluk and Floresco, 2009 ; Klanker et al, 2013 ; Radke et al, 2019 ; Tomm et al, 2022 ); as orexin neurons project to the VTA (Peyron et al, 1998 ), understanding how these neural substrates interact could provide more clarity on sex differences in cognitive flexibility after stress. Furthermore, future research should more directly determine the role of gonadal hormones in these circuits, which would lead to a more comprehensive understanding of sex differences in cognitive flexibility.…”

“…However, another rodent study has shown that in ovariectomized female rats, 17β-estradiol treatment results in poorer learning in simple discrimination but improved learning in extradimensional set-shifting (Lipatova et al, 2016 ). Furthermore, in male rats, high testosterone has been reported to impair both extradimensional set-shifting and reversal learning (Wallin and Wood, 2015 ; Tomm et al, 2022 ). Thus, more research is necessary to better understand how changes in gonadal hormones may impact cognitive flexibility.…”

Androgens, brain and androgen deprivation therapy in paraphilic disorders: A narrative review

“…Testosterone and its active, nonaromatizable metabolite, dihydrotestosterone (DHT), are synthesized in both the testes (O'Donnell et al, 2022) and the brain (Brandt et al, 2020; Fester & Rune, 2021) including the medial prefrontal cortex and other nodes of the mesocorticolimbic system (Tomm et al, 2022). Circulating testosterone can bind and activate the classical nuclear ARs directly or indirectly through DHT (McEwan & Brinkmann, 2000).…”

“…T also participates in the excitatory and inhibitory processes of sexual functions, modulating the activity of neurotransmitter systems, especially dopaminergic (Jordan et al, 2011a; Bell & Sisk, 2013) and opioid peptides (Sharp et al, 2022). Recently, it has been observed that T neurally‐produced increased dopamine signalling in the mesocorticolimbic system (Tomm et al, 2022) and in the extrapyramidal system (Przybylska et al, 2021).…”