Chronic social stress (SS) is associated with urinary bladder dysfunction. In vivo urodynamic studies revealed that stressed rats had increased bladder capacity, elevated micturition volume, prolonged interval between micturition, and non-micturition-related contractions that mimicking detrusor overactivity. Ketamine is an antagonist of the N-methyl-D-aspartic acid (NMDA) receptor complex. A sub-anesthetic dose of ketamine could produce a rapid and long-lasting antidepressant effect in animal studies. Therefore, ketamine was supposed to relieve SS and then ameliorate stress-induced disorders. The aim of the study is to investigate whether ketamine could ameliorate social stress (SS) related bladder dysfunction in mice.

The FVB mice were randomly assigned to either undergo SS exposure for 60 mins per day on seven consecutive days for 4 weeks (SS1) or control without SS (SS0). During each SS exposure, an intruder FVB mouse was placed into the home cage territory of an unfamiliar C57BL/6 resident with high aggression until C57BL/6 mice initiated aggressive behavior (e.g., biting sufficiently to break the skin). SS is defined as the FVB mouse assumed a supine posture after defeat by C57BL/6 resident. Following defeat, a wire mesh partition was placed in the cage to prevent physical contact between the resident and intruder. Auditory, olfactory, and visual contacts continued between FVB and C57BL/6 resident mice for 60 minutes. Control mice was placed in a novel cage behind a wire partition for 60 minutes daily. Mice were sent back to their home cage after each session. The SS0 were then allocated to single or no injection of ketamine (SS0K1 and SS0K0). In the group of SS1, the SS1 mice were allocated to receive single injection of saline (SS1K0), single dose (SS1K1) or 5 daily dose of (SS1K5) ketamine injection (25 mg/kg/day/ip) since Day 22. On Day 29, in vivo cystometry was performed at the end of 4-week SS exposure in both social stressed and non-stressed groups. Then, the urinary bladder was isolated and cut into strips and mounted in the organ bath for measurement of detrusor activity. Serum and urine level of brain-derived-neurotrophic factor (BDNF) were measured with ELISA. The bladder sections were stained with hematoxylin and eosin to assess morphology. The following chemicals were used: NaCl, NaHCO3, KCl, CaCl2, MgCl2, and glucose, NaH2PO4, EDTA, Acetylcholine, lidocaine, silodosin, norepinephrine, Rat BDNF ELISA Kit (all from Sigma-Aldrich, ST Louis, MO, USA). A paired t-test was used to compare difference in the same strip. An ANOVA of variance followed by post-hoc tests (Bonferroni) was used to compare difference between different strips. All values are presented as mean ± SEM. A value of p < 0.05 was considered statistically significant.

In mice without social stress exposure, ketamine administration did not significantly affect voiding frequency (SS0K0 vs. SS0K1 = 3.0±0.3 vs 3.5±0.3., p>0.05). SS1K0, SS1K1 and SS1K5 had significantly lower voiding frequency than that of control (SS1K0) (0.4±0.2, 1.4±0.2, and 1.0±0.3 vs. 3.0±0.3; each n=15, p<0.05). However, ketamine administration reversed the trend of decreased voiding frequency in SS1 mice. As compared to SS0K0, SS1K0 had higher serum, but not urine, levels of BDNF. The higher serum level of BDNF in SS1K0 significantly lowered in SS1K1. Urodynamic studies revealed that all SS1 groups had detrusor overactivity and impaired detrusor contractility which were not reversed by short-term ketamine. In bladder strips undergoing HE stain, the urothelium and detrusor muscle disclosed no significant difference between the 4 groups of mice. Tissue bath wire myography studies revealed that the contractility of UB strips of SS1K0, SS1K1 and SS1K5 were significantly lower than that of control (SS0K0) (n=6, p<0.05) while ketamine did not pose impact on detrusor contractility. In the meantime, the relaxations of detrusor muscle were not affected by SS and ketamine.

Social stress leads to elevated serum BDNF, infrequent voiding, detrusor overactivity and impaired contractility while no morphological change was observed. Short-term administration of ketamine may improve social stress related infrequent voiding and elevated serum BDNF level. However, ketamine did not improve SS related bladder dysfunction on urodynamic and tissue bath wire myography studies.

Social stress leads to bladder dysfunction and short-term administration of ketamine may temporarily relieve stress but cannot improve stress related bladder dysfunction.

Mingin GC, Peterson A, Erickson CS, Nelson MT, Vizzard MA. Social stress induces changes in urinary bladder function, bladder NGF content, and generalized bladder inflammation in mice. Am J Physiol Regul Integr Comp Physiol. 2014; 307(7): R893-900.
Mingin GC, Heppner TJ, Tykocki NR, Erickson CS, Vizzard MA, Nelson MT. Social stress in mice induces urinary bladder overactivity and increases TRPV1 channel-dependent afferent nerve activity. Am J Physiol Regul Integr Comp Physiol. 2015; 309(6): R629-38.
Garcia LS, Comim CM, Valvassori SS, Reus GZ, Barbosa LM, Andreazza AC, et al. Acute administration of ketamine induces antidepressant-like effects in the forced swimming test and increases BDNF levels in the rat hippocampus. Prog Neuropsychopharmacol Biol Psychiatry. 2008; 32(1): 140-4.