Serotonin and Noradrenaline Reuptake Inhibitors Improve Micturition Control in Mice

Poor micturition control may cause profound distress, because proper voiding is mandatory for an active social life. Micturition results from the subtle interplay of central and peripheral components. It involves the coordination of autonomic and neuromuscular activity at the brainstem level, under the executive control of the prefrontal cortex. We tested the hypothesis that administration of molecules acting as reuptake inhibitors of serotonin, noradrenaline or both may exert a strong effect on the control of urine release, in a mouse model of overactive bladder. Mice were injected with cyclophosphamide (40 mg/kg), to increase micturition acts. Mice were then given one of four molecules: the serotonin reuptake inhibitor imipramine, its metabolite desipramine that acts on noradrenaline reuptake, the serotonin and noradrenaline reuptake inhibitor duloxetine or its active metabolite 4-hydroxy-duloxetine. Cyclophosphamide increased urine release without inducing overt toxicity or inflammation, except for increase in urothelium thickness. All the antidepressants were able to decrease the cyclophosphamide effects, as apparent from longer latency to the first micturition act, decreased number of urine spots and volume of released urine. These results suggest that serotonin and noradrenaline reuptake inhibitors exert a strong and effective modulatory effect on the control of urine release and prompt to additional studies on their central effects on brain areas involved in the social and behavioral control of micturition.

排尿（micturition）控制不佳可能引发剧烈的痛苦困扰，因为正常排尿是维持积极社交生活的必要条件。排尿源于中枢与外周组分间的精妙相互调控，涉及脑干水平上自主神经与神经肌肉活动的协调，并受前额叶皮层（prefrontal cortex）的执行调控。本研究在膀胱过度活动症（overactive bladder）小鼠模型中验证了如下假说：给予5-羟色胺（serotonin）、去甲肾上腺素（noradrenaline）或二者的再摄取抑制剂类分子，可对排尿控制产生显著影响。

研究人员向小鼠注射环磷酰胺（cyclophosphamide，40 mg/kg）以增加排尿频次，随后分别给予四种受试分子：5-羟色胺再摄取抑制剂丙米嗪（imipramine）、作用于去甲肾上腺素再摄取的其代谢物地昔帕明（desipramine）、兼具5-羟色胺与去甲肾上腺素再摄取抑制作用的度洛西汀（duloxetine），及其活性代谢产物4-羟基度洛西汀（4-hydroxy-duloxetine）。

环磷酰胺可提升排尿量，且未引发明显毒性或炎症反应，仅造成尿路上皮（urothelium）厚度增加。所有受试抗抑郁药均能削弱环磷酰胺的作用，具体表现为首次排尿潜伏期延长、尿斑数量减少以及排尿量降低。

上述结果表明，5-羟色胺与去甲肾上腺素再摄取抑制剂可对排尿控制产生强效且有效的调节作用，提示未来应开展更多相关研究，以探究其对参与排尿社交与行为调控的脑区的中枢效应。