Subthalamic Stimulation-Induced Forelimb Dyskinesias Are Linked to an Increase in Glutamate Levels in the Substantia Nigra Pars Reticulata

Abstract

The neurobiological mechanisms by which high-frequency stimulation of the subthalamic nucleus (STN-HFS) alleviates the motor symptoms of Parkinson's disease (PD) remain unclear. In this study, we analyzed the effects of STN-HFS on motor behavior in intact or hemiparkinsonian rats (6-hydroxydopamine lesion of the substantia nigra pars compacta) and investigated the correlation between these effects and extracellular glutamate (Glu) and GABA levels, assessed by intracerebral microdialysis in the substantia nigra pars reticulata (SNr). STN-HFS at an intensity corresponding to the threshold inducing contralateral forelimb dyskinesia, increased Glu levels in the SNr of both intact and hemiparkinsonian rats. In contrast, STN-HFS at half this intensity did not affect Glu levels in the SNr in intact or hemiparkinsonian rats but increased GABA levels in hemiparkinsonian rats only. STN-HFS-induced forelimb dyskinesia was blocked by microinjection of the Glu receptor antagonist kynurenate into the SNr and facilitated by microinjection of a mixture of the Glu receptor agonists AMPA and NMDA into the SNr. These new neurochemical data suggest that STN-HFS-induced forelimb dyskinesia is mediated by glutamate, probably via the direct activation of STN axons, shedding light on the mechanisms of STN-HFS in PD.

Stimulation-Induced Dyskinesias Inform Basal Ganglia Models and the Mechanisms of Deep Brain Stimulation: Figure 1.

“…Despite its success, it is still not clear how HFS changes activity in the brain to achieve its clinical effect. Recent work by Boulet et al (2006) in The Journal of Neuroscience supports previous studies finding that HFS activates the target structure. Further, it provides new evidence suggesting that dyskinesias (a common side-effect of long-term dopaminereplacement therapy for PD as well as high-intensity HFS) are correlated with increases in glutamate in the substantia nigra pars reticulata (SNr).…”

“…The primary findings of Boulet et al (2006) are as follows: (1) HFS stimulation at a threshold intensity for the induction of forelimb dyskinesia (stimulation amplitude I 1 ) resulted in increased extracellular SNr glutamate during and after HFS in both intact and 6-OHDA-lesioned rats [Boulet et al (2006) Given that the glutamate levels in the SNr appear to derive primarily from STN activity (Rosales et al, 1997), the increases in extracellular glutamate during and after HFS support the concept that HFS activates the target structure. However, it cannot be deduced from the work of Boulet et al (2006) whether this increase is necessary for clinical improvement, because data were not included regarding the physical state of the rats (such as increased number of nondyskinetic movements during HFS). Boulet et al (2006) also found that GABA levels could be increased by HFS, and that AMPA and NMDA injections into the SNr alone are not sufficient to induce dyskinesias.…”

“…HFS may decouple axonal activity from somatic activity, with somatic activity inhibited by HFS, but axonal output increased (McIntyre et al, 2004), which could explain these disparate findings. Boulet et al (2006) used 6-OHDA to model PD in rats by selectively lesioning the substantia nigra pars compacta (SNc), which represents the dopaminergic input to the dorsal striatum and BG. They simulated HFS by stimulating at 130 Hz via implanted microelectrodes in the STN in both 6-OHDA-lesioned rats and a control group with an intact SNc.…”

“…Boulet et al (2006) describe four categories of dyskinesias that were observed in the 6-OHDA-lesioned group and in the control group as the amount of stimulating current was increased [Boulet et al (2006) The authors focused their attention on forelimb dyskinesias, presumably because these most nearly approximate the hand and foot dyskinesias, which are most disabling in PD patients. Thus, it is unclear whether the results also would apply to other types of dyskinesia.…”

Mechanisms and Targets of Deep Brain Stimulation in Movement Disorders

“…54 These studies have also shown that elevated GABA levels depend on the frequency of stimulation, closely mimicking the frequency-response curves reported in clinical applications of DBS. 52 Boulet et al 55 suggested that neurochemical effects of HFS also depend on the amplitude of stimulation and whether or not the subject is parkinsonian. At high stimulation amplitudes (75-200 A), sufficient to evoke contralateral forelimb dyskinesias, STN HFS increased glutamate and GABA in the SNr of intact rats, but only glutamate in the SNr of 6-hydroxydopamine (6-OHDA) lesioned rats.…”