Fig. 5.
A hypothetical diagram demonstrates working model of bladder dysfunction in PD. Micturition reflex is controlled by spinobulbospinal pathways through PAG in midbrain and PMC in brainstem. This neural circuit is under control of higher centers, including anterior cingulate cortex (ACC) and other cortex regions. (A) Under normal conditions tonic inhibition from ACC suppress micturition reflex. Tonic firing (+) of dopaminergic neurons in SN activates dopamine D1 receptors expressed on GABAergic inhibitory neurons in the striatum to induce tonic GABAergic inhibition (−) of the micturition reflex at the level of PAG. At the same time, D1 receptor stimulation suppresses the activity of adenosinergic neurons, which exert an excitatory effect on micturition via adenosine A2A receptors (+). (B) In PD, dopaminergic neurons in the substantia nigra pars compacta (SN) are lost (lesion), leading to the loss of dopamine D1 receptors activation (D1 [loss of activation]), which results in reduced activation inhibitory GABAergic neurons in the striatum (GABA [loss of inhibition]). At the same time, reduced D1 receptor stimulation enhances the adenosinergic mechanism to stimulate adenosine A2A receptors (adenosine A2A [++]), leading to facilitation of the spinobulbospinal pathway controlling the micturition reflex pathway. Administration of dopamine D1 receptor agonist (SKF 38393) can restore the GABAergic nerve activity and suppress A2A receptor-mediated activation to reduce bladder overactivity in PD. Also, administration of adenosine A2A antagonists (ZM241385 or istradefylline) can suppress A2A receptor-mediated activation of the micturition reflex to reduce bladder overactivity in PD. Dopamine D2 receptors (D2 [+]) expressed in the spinal cord enhances the micturition reflex.
(Modified from Kitta T, Chancellor MB, de Groat WC, et al. Role of the anterior cingulate cortex in the control of micturition reflex in a rat model of Parkinson's disease. J Urol 2016;195:1613–20.)