Application of 4-aminopyridine (4AP, 50 microM) to combined slices of adult rat hippocampus-entorhinal cortex-induced ictal and interictal epileptiform discharges, as well as slow field potentials that were abolished by the mu-opioid agonist [D-Ala2,N-Me-Phe4,Gly-ol5] enkephalin (DAGO, 10 microM) or the GABAA receptor antagonist bicuculline methiodide (BMI, 10 microM); hence, they represented synchronous GABA-mediated potentials. Ictal discharges originated in the entorhinal cortex and propagated to the hippocampus, whereas interictal activity of CA3 origin was usually recorded in the hippocampus. The GABA-mediated potentials had no fixed site of origin or modality of propagation; they closely preceded (0.2-5 sec) and thus appeared to initiate ictal discharges. Only ictal discharges were blocked by the antagonist of the NMDA receptor 3,3-(2-carboxypiperazine-4-yl)propyl-1-phosphonate (CPP, 10 microM), whereas the non-NMDA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, 10 microM) abolished all epileptiform activities. The GABA-mediated potentials continued to occur synchronously in all regions even after concomitant application of CNQX and CPP. [K+]o elevations were recorded in the entorhinal cortex during the ictal discharge (peak values = 13.9 +/- 0.9 mM) and the synchronous GABA-mediated potentials (peak values = 4.2 +/- 0.1 mM); the latter increases were presumably attributable to postsynaptic GABAa-receptor activation because they were abolished by DAGO or BMI. Their role in initiating ictal activity was demonstrated by using DAGO, which abolished both GABA-mediated synchronous potentials and ictal discharges. These data indicate that NMDA-mediated ictal discharges induced by 4AP originate in the entorhinal cortex; such a conclusion is in line with clinical evidence obtained in temporal lobe epilepsy patients. 4AP also induces GABA-mediated potentials that spread within the limbic system when excitatory transmission is blocked and may play a role in initiating ictal discharge by increasing [K+]o.
Abbreviations & Acronyms A = adrenergic/noradrenergic BBB = blood-brain barrier DA = dopamine DLTN = dorsolateral tegmental nucleus DO = detrusor overactivity GABA = gamma-amino-butyric acid Glu = glutamate. GPi = globus pallidus internus IML = intermediolateral cell column L = lumbar LC = locus ceruleus LUT = lower urinary tract LUTS = lower urinary tract symptoms MPOA = medial preoptic area MSA = multiple system atrophy NBM = nucleus basalis Meynert OAB = overactive bladder PAG = periaqueductal gray matter PBN = parabrachial nucleus PD = Parkinson's disease PMC = pontine micturition center PVN = paraventricular nucleus S = sacral SNc = substantia nigra pars compacta SNr = substantia nigra pars reticulata STN = subthalamic nucleus T = thoracic TUR-P = transurethral prostate resection of the prostate VTA = ventral tegmental area ZI = zona incerta Abstract: Bladder function of patients with Parkinson's disease alters significantly: the majority of patients have overactive bladder (urinary urgency/frequency) with little or no post-void residuals. This seems to be the result of an altered brain-bladder relationship, as in Parkinson's disease, the frontal-basal ganglia D1 dopaminergic circuit that normally suppresses the micturition reflex is altered. The pathophysiology of the bladder dysfunction in Parkinson's disease differs from that in multiple system atrophy; therefore, it might also aid in differential diagnosis. The effects of levodopa, the major drug to treat motor dysfunction, on the bladder in Parkinson's disease vary significantly; therefore, add-on therapy is often required. Anticholinergic drugs are the first-line treatment, with particular care for cognitive function in elderly patients. The second-line treatment includes serotonergics drug, desmopressin and others. Newer modalities include deep brain stimulation that improves the bladder in Parkinson's disease; and botulinum toxin is promising, particularly in difficult cases. These treatments might be beneficial in maximizing the patients' quality of life.
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