Description: The rat dorsal striatum exhibits domain-dependent kinetics of dopamine release and clearance. The present report describes the domain-dependent actions of nomifensine (20 mg/kg i.p.), a competitive dopamine uptake inhibitor, on evoked dopamine responses recorded by voltammetry during electrical stimulation of the medial forebrain bundle. In slow domains, nomifensine increases the initial rate of evoked overflow, increases response overshoot, does not affect the slope of the linear segment of the dopamine clearance profile, and slows the non-linear segment of the clearance profile. In fast domains, nomifensine does not affect the initial rate of overflow, increases the end-of-stimulus overshoot, and decreases the slope of the linear segment of the dopamine clearance profile. Collectively, these findings do not concur with existing models of evoked dopamine release that describe the effect of nomifensine as an increase in the effective K M of dopamine uptake. These findings suggest that dopamine clearance after evoked release is affected by both dopamine uptake and a restricted extracellular diffusion process. © 2012 The Authors Journal of Neurochemistry © 2012 International Society for Neurochemistry

Description: Dopamine (DA), a highly significant neurotransmitter in the mammalian central nervous system, operates on multiple time scales to affect a diverse array of physiological functions. The significance of DA in human health is heightened by its role in a variety of pathologies. Voltammetric measurements of electrically evoked dopamine release have brought to light the existence of a patchwork of DA kinetic domains in the dorsal striatum of the rat. Thus, it becomes necessary to consider how these domains might be related to specific aspects of DA's functions. Responses evoked in the fast and slow domains are distinct in both amplitude and temporal profile. Herein we report that responses evoked in fast domains can be further classified into four distinct types, types 1-4. The dorsal striatum, therefore, exhibits a total of at least five distinct evoked responses (4 fast types and 1 slow type). All five response types conform to kinetic models based entirely on first order rate expressions, which indicates that the heterogeneity among the response types arises from kinetic diversity within the dorsal striatum terminal field. We report also that functionally distinct sub-regions of the dorsal striatum express DA kinetic diversity in a selective manner. Thus, this study documents five response types, provides a thorough kinetic explanation for each of them, and confirms their differential association with functionally distinct sub-regions of this key DA terminal field. This article is protected by copyright. All rights reserved.

Description: Many neurodegenerative diseases are characterized by the formation of microscopically visible intracellular protein aggregates. α-Synuclein is the key aggregating protein in Parkinson's disease which is characterized by neuronal cytoplasmic Lewy body inclusions. Previous studies have shown relative sparing of neurons in Parkinson's disease and dementia with Lewy bodies that are positive for the vitamin D-dependent calcium buffering protein, calbindin-D28k and that α-synuclein aggregates are excluded from calbindin-D28k-positive neurons. Recent cell culture studies have shown that α-synuclein aggregation can be induced by raised intracellular free Ca(II) and demonstrated that raised intracellular calcium and oxidative stress can act synergistically to promote α-synuclein aggregation. We hypothesized that calcipotriol, a potent vitamin D analogue used pharmaceutically, may be able to suppress calcium-dependent α-synuclein aggregation by inducing calbindin-D28k expression. Immunofluorescence and Western blot analysis showed that calcipotriol potently induced calbindin-D28k in a dose dependent manner in SH-SY5Y human neuroblastoma cells. Calcipotriol significantly decreased the frequency of α-synuclein aggregate positive cells subjected to treatments that cause raised intracellular free Ca(II) (potassium depolarization, KCl/H 2 O 2 combined treatment and rotenone) in a dose dependent manner and increased viability. Suppression of calbindin-D28k expression in calcipotriol-treated cells using calbindin-D28k-specific siRNA showed significantly higher α-synuclein aggregation levels, indicating that calcipotriol -mediated blocking of calcium-dependent α-synuclein aggregation was dependent on the induction of calbindin-D28k expression. These data indicate that targeting raised intraneuronal free Ca(II) in the brain by promoting the expression of calbindin-D28k at the transcriptional level by using calcipotriol could prevent α-synuclein aggregate formation and ameliorate Parkinson's disease pathogenesis. This article is protected by copyright. All rights reserved.