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Effects of gonadectomy and inhibition of of androgen synthesis on behavioural flexibility in male rats Tomm, Ryan Justin

Abstract

Androgens regulate sexual and aggressive behaviour in males. However, little attention has focused on the effects of androgens on executive function. Androgens are produced in the gonads but are also produced in the brain, which might be important when systemic androgen levels are low. Here, we examined the effects of gonadectomy (GDX) and/or an androgen synthesis inhibitor (abiraterone acetate, ABI) on different forms of behavioural flexibility in adult male Long-Evans rats. Rats received either GDX or Sham surgeries and then were housed for 5 weeks, to allow for upregulation of local androgen synthesis after GDX. Five days prior to the commencement of behavioural training, rats received daily treatments of either Vehicle or ABI (40 mg/kg, p.o.), an androgen synthesis inhibitor that crosses the blood-brain barrier. Behavioural flexibility was assessed on an operant based strategy set-shifting task or a spatial reversal learning task. The strategy set-shifting task required rats to disengage from a previously correct (but now incorrect) visual-cue based discrimination strategy, and acquire and maintain a new egocentric spatial response strategy. During the set-shift to an egocentric response strategy, ABI treatment (but not GDX) caused an improvement in behavioural flexibility, by reducing the number of errors made before reaching criterion. In a separate group of rats trained on a reversal learning task, we found a similar effect, in that only ABI reduced perseverative-type errors during the reversal. During the set-shift and the response reversal, there were no effects of GDX, suggesting that GDX+Vehicle subjects maintain or upregulate neural androgen synthesis to maintain baseline flexibility. Using liquid chromatography tandem mass spectrometry, we measured testosterone (T) in the medial prefrontal cortex (mPFC) and the dorsomedial striatum (DMS). Neural T was only detectable in the Sham+Vehicle rats, suggesting that GDX+Vehicle rats may have neural T synthesis occurring in other brain regions important for behavioural flexibility. Taken together, these data suggest that neural T synthesis may serve to increase persistence of behaviour, which can in some instances suppress behavioural flexibility.

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