Underactive bladder(UAB) is a type of lower urinary tract symptoms, which is common in benign prostate hyperplasia, diabtes mellitus and those undertaken pelvic surgery such as radical hysterectomy.  The aetiology of UAB can be concluded as neurogenic, muscular and vascular. Currently, there is no effective treatment to reverse the bladder damage or increase the bladder contractile. Serotonin has been recognized as a crucial neural transmitter in the regulation of micturition reflex. Our previous studies demonstrated that DOI, a 5-HT2A/2C receptor agonist could improve voiding dysfunction in diabetic rats. Besides, serotonin is found existing in the bladder and urethra, and may be a factor for UAB in the aging rats. Thus, this study aims to explore the effect of DOI in the rats with neurogenic underactive bladder and the underlying mechanism.

Twenty male Sprague dawley rats were divided into the normal group (n=10) and the neurogenic underavtive bladder group(NUAB, n=10). The NUAB rat model was established by transected of bilateral pelvic nerves. Ten days after the surgery, half of the rats were anesthetized by urethane(1.3g/kg), and then undertaken cystometrogram(CMG) test. An increasing dose of 0.03~1.00 mg/kg of DOI were administrated intravenously in both normal and NUAB rats. Dose-dependent curves of CMG parameters were recorded. The remaining rats were executed and the tissues (bladder and urethra) were collected for histological study. The level of serotonin and 5-HT2A/2C receptors were examined by ELISA and immunostaining respectively.

The CMG test of UAB rats showed decreased voiding volume, voiding efficiency, increased residual volume, and the HE staining of bladder showed increased capacity and muscle layer hypertrophy, indicating the compensatory change due to detrusor underactivity. Further, DOI can dose-dependently increase the voiding efficiency of NUAB rats with increased amplitude of bladder contraction, voiding volume and decreased residual volume, whereas DOI had insignificant effect on normal rats. The results of ELISA and immunostaining showed that the 5-HT and 5-HT2A receptor were significantly increased in bladder in NUAB rats compared to normal rats, whereas 5-HT were decreased and 5-HT2A receptor were increased in urethra.

First, our results showed that the NUAB rat model could be successfully established by transection of bilateral pelvic nerve. Second, 5-HT2A/2C receptor agonist (DOI) could significantly increase bladder contractility and thus improve voiding efficiency. Finally, the ELISA and immunostaining results indicate that the change of serotonin and 5-HT2A receptor in both bladder and urethra may be the underlying mechanism of this phenomenon, supporting the urethra-to-bladder reflex theory.

5-HT2A/2C receptor agonist (DOI) could significantly increase the amplitude of bladder contraction, voiding volume and voiding efficiency of rats with neurogenic underactive bladder. Increased 5-HT2A receptor in the bladder and urethra indicated the urethra-to-bladder reflex may be the crucial mechanism of this phenomenon.

Continence 7S1 (2023) 100969
DOI: 10.1016/j.cont.2023.100969