Differential effects of prolonged high frequency stimulation and of excitotoxic lesion of the subthalamic nucleus on dopamine denervation‐induced cellular defects in the rat striatum and globus pallidus

Abstract

This study examined the effects of prolonged (4 days) high frequency stimulation (HFS) of the subthalamic nucleus (STN), in comparison with those of STN lesion, on the dopamine denervation-mediated cellular changes in the basal ganglia in a Wistar rat model of Parkinson's disease. STN HFS counteracted the dopamine lesion-induced increase in GAD67 mRNA expression in the output structures of the basal ganglia, as shown previously after STN lesion, providing cellular support for the similar antiparkinsonian benefits produced by the two surgical procedures. The dopamine denervation-induced increase in GAD67 mRNA levels in the globus pallidus was partially antagonized after HFS and totally reversed after ibotenate-induced STN lesion. The overexpression of striatal enkephalin mRNA tended to be further increased by HFS but was antagonized by STN lesion. The decrease in striatal substance P mRNA levels was affected neither by STN HFS nor lesion. As STN HFS for two hours was previously found not to interfere with the effects of dopamine lesion in the globus pallidus and striatum, the present data provide strong evidence that the effects of STN surgery in these structures involve long-term adaptive processes and that the rearrangements mediated by HFS and lesion are, at least in part, different.

High-Frequency Stimulation of the Subthalamic Nucleus Potentiates l-DOPA-Induced Neurochemical Changes in the Striatum in a Rat Model of Parkinson's Disease

“…This finding can be compared with recent data showing that STN-HFS (2-4 h) induces immediateearly gene expression in the motor cortex (Schulte et al, 2006). The cortical activation could be the consequence of an excitation, and additional antidromic invasion, of corticosubthalamic axons, because the areas examined are known to send projections to STN (Orieux et al, 2002), or be linked to the rapid normalization of the cellular changes in the basal ganglia output structures (Salin et al, 2002;Tai et al, 2003;Bacci et al, 2004;Degos et al, 2005). In the striatum, we confirm our previous finding that prolonged STN-HFS per se does not modify the dopamine lesion-induced changes in PPE and PPT mRNA levels (Bacci et al, 2004), and we show that it does not modify either the postlesional decrease in PPD mRNA levels nor affected GLT1 gene expression and FosB/⌬FosB immunoreactivity.…”

“…This evaluation was performed 12 h after the last injection of L-DOPA for the DOPA/HFS and DOPAϩHFS groups, the latter receiving the next injection just afterward. As described previously (Salin et al, 2002;Bacci et al, 2004;Boulet et al, 2006), STN-HFS at increasing intensity induced per se a sequence of AIMs as follows: orofacial dyskinetic movements (from ϳ110 A in our experimental conditions), plus dyskinetic movements of the contralateral forelimb (from 130 A), plus strong contralateral bias in the head position, and finally contralateral rotation (from 170 A). Therefore, the different subtypes of L-DOPA-induced AIMs can be induced sequentially by STN-HFS.…”

“…The mean OD value was determined from four sections per animal after subtracting the background signal measured on each section by scanning a corpus callosum area that is known to lack DA terminals. The location of the stimulating electrode in the STN of HFS groups was examined on cresyl-violet-stained sections: we considered the correct location when the anterior and posterior wires were both in the STN (see also Bacci et al, 2004). Animals showing a reduction of Ͻ85% in 3 H-mazindol binding or a misplaced electrode were not included in the experimental groups presented above.…”

“…As described previously (Bacci et al, 2004), the electrode was formed by two parallel platinum iridium wires insulated with Teflon and bared at the extremity at a length of 500 m (diameter of each wire: 140 m insulated, 76 m bare). The distance between the two wires was ϳ500 m. The electrode was implanted so that the two wires were placed in the anteroposterior axis, and the bared part of each wire was covering the STN extent in depth.…”

“…Short-duration STN-HFS increases striatal glutamate extracellular levels (Bruet et al, 2003) and enhances dopamine release and metabolism (Bruet et al, 2001;Meissner et al, 2003;Lee et al, 2006). However, neither short duration nor prolonged STN-HFS significantly affects the dopamine lesion-induced increase in striatal PPE or preprotachykinin (PPT) mRNA expression (Salin et al, 2002;Bacci et al, 2004).…”