Abstract
Although the potent anti-parkinsonian action of the atypical D1-like receptor agonist SKF83959 has been attributed to the selective activation of phosphoinositol(PI)-linked D1 receptor, whereas the mechanism underlying its potent neuroprotective effect is not fully understood. In the present study, the actions of SKF83959 on neuronal membrane potential and neuronal excitability were investigated in CA1 pyramidal neurons of rat hippocampal slices. SKF83959 (10–100 µM) caused a concentration-dependent depolarization, associated with a reduction of input resistance in CA1 pyramidal neurons. The depolarization was blocked neither by antagonists for D1, D2, 5-HT2A/2C receptors and α1-adrenoceptor, nor by intracellular dialysis of GDP-β-S. However, the specific HCN channel blocker ZD7288 (10 µM) antagonized both the depolarization and reduction of input resistance caused by SKF83959. In voltage-clamp experiments, SKF83959 (10–100 µM) caused a concentration-dependent increase of Ih current in CA1 pyramidal neurons, which was independent of D1 receptor activation. Moreover, SKF83959 (50 µM) caused a 6 mV positive shift in the activation curve of Ih and significantly accelerated the activation of Ih current. In addition, SKF83959 also reduced the neuronal excitability of CA1 pyramidal neurons, which was manifested by the decrease in the number and amplitude of action potentials evoked by depolarizing currents, and by the increase of firing threshold and rhoebase current. The above results suggest that SKF83959 increased Ih current through a D1 receptor-independent mechanism, which led to the depolarization of hippocampal CA1 pyramidal neurons. These findings provide a novel mechanism for the drug's neuroprotective effects, which may contributes to its therapeutic benefits in Parkinson's disease.
Highlights
SKF83959 (3-methyl-6-chloro-7,8-hydroxy-1-[3-methylphenyl] -2,3,4,5-tetrahydro-1H-3- benzazepine) is a selective agonist for the putative phosphatidylinositol (PI)-linked D1-like receptor [1,2,3]
In the present study we characterized the electrophysiological effects of SKF83959, an atypical D1-like receptor agonist, on the passive membrane properties and excitability of hippocampal CA1 pyramidal neurons
In the present study we demonstrate that SKF83959 causes a concentration-dependent depolarizing response in rat hippocampal CA1 pyramidal neurons
Summary
SKF83959 (3-methyl-6-chloro-7,8-hydroxy-1-[3-methylphenyl] -2,3,4,5-tetrahydro-1H-3- benzazepine) is a selective agonist for the putative phosphatidylinositol (PI)-linked D1-like receptor [1,2,3]. It has been demonstrated that SKF83959 produces no cAMP formation in brain tissues but induces PI-hydrolysis via activation of the PI-linked D1-like receptor/Gq protein/PLCb signaling pathway[1,2,3,4,5]. The anti-parkinsonian action of SKF83959 has been attributed to activation of PI-linked D1-like receptor [1,8,9,11], the exact mechanisms underlying the action remain unclear. Our previous work demonstrated that SKF83959 exerted a potent neuroprotective action in rat pheochromocytoma cells (PC12 cells) treated with H2O2 [12]. This action, was only partially attributed to inhibition of glycogen synthase kinase-
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
