AbstractThis thesis investigates the effects of psychological stress on bladder function in mice and the potential benefit of current clinical therapies. Psychological stress and bladder dysfunction encompass a wide range of disorders known to affect a large portion of the society. There is convincing clinical evidence that links psychological stress with bladder dysfunction, but the underlying physiological mechanisms involved, and suitability of drug treatments, remain elusive. The effects of social stress, witness stress and environmental stress on bladder function were observed using a social defeat and witness trauma model, as well as a water avoidance stress model, with animals exposed to stress for 1 h/day for 10 consecutive days. These models were used to investigate the effects on voiding behaviour and local bladder function.
Social defeat but not witness trauma stress decreased urinary frequency in male mice, indicative of urinary retention, which could be due to the increase in purinergic responses observed in the isolated whole bladder preparations from these mice. In contrast, the water avoidance model produced increased urinary frequency in female mice and an increase in overall contractility of the bladder. Due to the clinical association between psychological stress and overactive bladder (OAB), rather than urinary retention, recovery studies were completed in the water avoidance stress model, as were drug treatment studies using the anxiolytic sertraline and commonly used OAB drugs mirabegron and solifenacin.
Ten-days stress-free recovery increased bladder compliance in water avoidance stressed animals and reduced urinary frequency, although not back to unstressed control levels, with a new elevated baseline evident. All drug treatments decreased the hormonal response to stress, measured as plasma corticosterone levels, and decreased voiding dysfunction, measured as voiding frequency. Sertraline, however, reduced stress hormone levels the most, while also targeting the increased bladder contractility observed after psychological stress more efficiently. Despite this, mirabegron and solifenacin were more effective at reducing the impact of stress on urinary frequency, returning voiding behaviour to that of unstressed control animals.
Overall, bladder dysfunction induced by stress exposure appears to be dependent upon sex and/or stressor type; with urinary retention evident in male mice following social defeat, no voiding changes in male witness mice and development of an overactive phenotype in female mice after water avoidance stress. The bladder overactivity induced by water avoidance stress was associated with detrusor hypercontractility. Mirabegron and solifenacin were equally effective at reducing the impact of water avoidance stress on voiding behaviour and were both superior to the selective serotonin reuptake inhibitor sertraline.
|Date of Award||2021|
|Supervisor||Catherine McDermott (Supervisor), Donna Sellers (Supervisor) & Russ Chess-Williams (Supervisor)|