It is common that patients with Parkinson’s disease (PD) manifest various lower urinary tract symptoms (LUTS) [1]. In particular, overactive bladder (OAB) is usually severe in PD patients. However, the mechanisms by which severe OAB is evoked in PD patients are unclear. Recent functional imaging study suggested that prefrontal cortex (PFC) plays a significant role in regulating micturition reflex. PFC is thought to inhibit involuntary voiding during urinary storage phase via PAG which is known to have dense connections with PFC [2]. Furthermore, PFC receives dense dopaminergic, noradrenergic, and serotonergic projections from ventral tegmental area, locus coeruleus, and raphe nucleus, respectively, suggesting that catecholamine might play significant role in regulating micturition reflex in PFC. In addition, subthalamic nucleus deep brain stimulation (STN-DBS) were reported to improve OAB in PD patients by partially restoring the basal ganglia circuit which eventually lead to normalizing afferent projections from PAG [3]. We therefore aimed to clarify the effect of PAG stimulation of catecholamine levels in PFC and also aimed to elucidate the effect of STN-DBS by simultaneous stimulation of subthalamic nucleus and PAG.

Experiments were performed under urethane anesthesia in 6-hydroxydopamine hemi-lesioned PD rats (n=6). A single-lumen catheter was trans-urethrally inserted into the bladder to measure bladder pressure. Stimulation electrodes are inserted into left subthalamic nucleus and PAG. A concentric microdialysis probe was inserted into left PFC and extracellular fluid was collected at 10-min interval before stimulation, during PAG stimulation, during PAG+STN stimulation, and after cessation of stimulation. The catecholamine levels (dopamine, serotonin, norepinephrine and their metabolites) were measured by high-performance liquid chromatography. The average levels of catecholamines in the dialysates collected during the first 30 min before stimulation were defined as the basal levels, and the levels at the following points were evaluated as the ratios to the basal levels. Bladder inter-contraction intervals were measured before, during PAG stimulation, during PAG+STN stimulation, and after cessation of stimulation.

PAG stimulation significantly decreased bladder inter-contraction interval from 568.7±46.6s to 342.1±39.8s (p<0.01). Adding subthalamic stimulation to PAG stimulation tended to increase bladder inter-contraction interval from 342.1±39.8s to 412.6±40.1s without statistical significance (p=0.07). Bladder inter-contraction interval return to base line level (493.5±50.0s vs before stimulation p=0.32) after cessation of stimulation. PAG stimulation significantly decreased norepinephrine levels in PFC 20 min after stimulation and norepinephrine levels were basically significantly decreased during PAG+STN stimulation and after cessation of stimulation. Dopamine levels were significantly decreased during PAG+STN stimulation and 30 min after cessation of stimulation. (Figure)

PAG stimulation significantly decreased bladder inter-contraction interval with concomitant decrease in norepinephrine and dopamine levels in PFC, which might indicate that increased afferent projection from lower urinary tract lead to reduction in norepinephrine and dopamine levels in PFC and worsen urinary frequency in PD model rat. Because it is well known that locus coeruleus producing norepinephrine is degenerated in PD, the present result suggested that reduction in norepinephrine level also contribute to the pathogenesis of OAB in PD patients. This result also suggeted that the drugs which can increase norepinephrine levels in PFC such as serotonin norepinephrine reuptake inhibitor might be effective in treating OAB in PD patients. The present result indicated that increasing dopamine levels in PFC might improve OAB, which is compatible with several previous study that levodopa (dopamine precursor) is effective in treating OAB.
 Although adding subthalamic stimulation to PAG stimulation tended to increase bladder inter-contraction interval, these effects were not statistically significant and did not significantly change catecholamine levels in PFC. These results suggested that STN-DBS did not significantly normalize afferent projection from PAG in PD model rat.

PAG stimulation significantly decreased bladder inter-contraction interval with concomitant decrease in norepinephrine and dopamine levels in PFC. STN-DBS did not significantly normalize afferent projection from PAG in PD model rat.

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