Effects of high frequency stimulation of subthalamic nucleus on extracellular glutamate and GABA in substantia nigra and globus pallidus in the normal rat

Abstract

High frequency stimulation (130 Hz) of the subthalamic nucleus has dramatic beneficial motor effects in severe parkinsonian patients. However, the mechanisms underlying these clinical results remain obscure. The objective of the present work was to study the neurochemical changes induced in rats by high frequency stimulation of the subthalamic nucleus by using intracerebral microdialysis within its target structures. Our results show that high frequency stimulation of the subthalamic nucleus induces a significant increase of extracellular glutamate levels in the ipsilateral globus pallidus and substantia nigra while GABA was augmented only in the substantia nigra. These data suggest that functional effects induced by high frequency stimulation of the subthalamic nucleus might imply distal mechanisms involving the synaptic relationships with the subthalamic efferences. They question the current view that the direct inhibition of the subthalamic neurons is induced by high frequency stimulation.

Mechanisms and Targets of Deep Brain Stimulation in Movement Disorders

“…During STN HFS in human subjects with Parkinson's disease (PD), Stefani et al 50,51 detected an increase in pallidal cGMP, considered to be a secondary messenger in the glutamatergic signaling pathway, which was accompanied by improvement in clinical symptoms. Microdialysis studies during STN HFS in normal anesthetized rats detected elevated levels of 1) glutamate in both the substantia nigra pars reticulata (SNr) and the GP (rat analog of primate GPe), which is consistent with increased output from STN, 52,53 and 2) GABA in the SNr, which may be a secondary effect or a result of suprathreshold current spreading into pallidonigral fibers of passage. 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.…”

High Frequency Stimulation of the Subthalamic Nucleus Eliminates Pathological Thalamic Rhythmicity in a Computational Model

“…Alternatively, it is possible that high-frequency GPi activity develops under HFS of STN because HFS drives the efferent axons projecting from the site where it is applied, augmenting neurotransmitter release, as argued by Montgomery and Baker (2000). It has been shown, for example, that HFS of STN in normal rat leads to an increase in extracellular glutamate in GPi and the substantia nigra pars reticulata (SNr), to which STN is the primary source of excitatory afferents (Paul et al, 2000;Windels et al, 2000). This theory is also supported by studies in parkinsonian patients, which found inhibitory effects after microstimulation of GPi (Dostrovsky et al, 2000), as well as increases in blood oxygenation level-dependent signal in subcortical regions in functional magnetic resonance imaging during DBS of STN, suggesting overstimulation of STN targets (Jech et al, 2001).…”

“…A variety of recent experiments have called this viewpoint into question, however, by demonstrating that high-frequency stimulation (HFS) leads to enhanced activity in stimulated areas (Garcia et al, 2003) or downstream effects consistent with enhanced synaptic outputs from stimulated areas (Paul et al, 2000;Windels et al, 2000;Anderson et al, 2003;Hashimoto, 2003). This leads to a theoretical conundrum, as it is not at all clear how to explain the beneficial effects of DBS if its action is to enhance neuronal activity.…”

Network modulation by the subthalamic nucleus in the treatment of Parkinson's disease

“…Although the therapeutic outcome is similar for both these interventions, the mechanisms underlying STN lesioning and stimulation may be different (McIntyre et al, 2004a,b). Indeed, evidence from experimental animal models has suggested that neurochemical and physiologic changes with stimulation at the target site may not be explained simply by inhibition (Windels et al, 2000;Hashimoto et al, 2003). Nonetheless, neural recordings during DBS in awake patients have indicated that local inhibition is an important feature of therapeutic DBS (Dostrovsky and Lozano, 2002).…”