Abstract
Various demographic groups experience androgen deprivation (AD), which can significantly impact their quality of life. A prominent example is prostate cancer (PCa) patients undergoing AD therapy, commonly used to treat advanced stages of the disease. The deprivation of androgens is associated with numerous side effects attributable in part to neurobiological changes, including sexual dysfunction due to a loss of sexual desire, and depression. One neuropeptide system affected by AD is orexin, which plays a role in arousal and wakefulness. Rats that have been androgen-deprived exhibit a significant reduction in the number of orexinergic neurons in the lateral hypothalamus. Previous studies have highlighted that central administration of orexin increases sexual performance and alleviates depressive symptoms in intact rodents, suggesting orexin’s role in both male sexual behaviour and depression. This leads to the hypothesis that orexin is involved in androgen-dependent behaviours and that the loss of orexinergic neurons contributes to the sexual dysfunction and depressive-related behaviours observed in AD.
In this thesis, I examined the effects of subcutaneous administration of orexin A on sexual and anhedonic depressive-like behaviours in androgen-deprived male rats, as a model for men undergoing AD. Following orchiectomy, the rats exhibited significant impairments in sexual behaviours but showed no change in sucrose preference, a measure of anhedonia. After initial behavioural assessments, rats were randomly assigned to either the orexin group (ORX; n = 8) or the control group (n = 7). The ORX group received subcutaneous injections of 5 nmol/kg of orexin A dissolved in saline, while the control group received saline injections, both administered daily over an 8-day period. Behavioural tests were conducted twice during the treatment period to assess the impact of orexin A on sexual and depressive behaviours. Orexin administration did not improve sexual dysfunction but may have a minor effect on sucrose preference. Additionally, I examined neurobiological changes through immunohistochemical analysis of androgen receptor (AR) and estrogen receptor alpha (ERα) expression in brain regions associated with sexual behaviour and neurocognition, including the medial preoptic area (mPOA), bed nucleus of the stria terminalis (BNST), and the medial amygdala (MeA). The analysis revealed no significant differences between the ORX and control groups.
The results of this study suggest subcutaneous administration of orexin A at the dose and frequency used in this study does not alleviate sexual dysfunction induced by AD. These findings are valuable for exploring new therapeutic approaches for alleviating the side effects of AD and ultimately improving the quality of life for those affected by it.