Influence of the frequency parameter on extracellular glutamate and γ‐aminobutyric acid in substantia nigra and globus pallidus during electrical stimulation of subthalamic nucleus in rats

Abstract

High-frequency stimulation (HFS) of the subthalamic nucleus (STN) proves to be an efficient treatment for alleviating motor symptoms in Parkinson's disease (PD). However, the mechanisms of HFS underlying these clinical effects remain unknown. Using intracerebral microdialysis, we previously reported that HFS induces, in normal rats, a significant increase of extracellular glutamate (Glu) in the globus pallidus (GP in rats or GPe in primates) and the substantia nigra pars reticulata (SNr), whereas gamma-aminobutyric acid (GABA) was increased only in the SNr. Bradykinesia can be improved by STN stimulation in a frequency-dependent manner, a plateau being reached around 130 Hz. The aim of the present study was to determine whether neurochemical changes are also frequency dependent. Electrical STN stimulation was applied at various frequencies (10, 60, 130, and 350 Hz) in normal rats. The results show that, for Glu, the amplitude of increase detected in GP and SNr is maximal at 130 Hz and is maintained at 350 Hz. No modifications of GABA were observed in GP whatever the frequency applied, whereas, in SNr, GABA increased from 60 to 350 Hz. Our results provide new neurochemical data implicating STN target structures in deep-brain-stimulation mechanisms.

Invasive and Non-Invasive Stimulation in Parkinson’s Disease

“…Importantly, other studies focused on the effects that DBS of the STN exerts on related nuclei of the basal ganglia. Supporting increased excitatory action of the STN elevated levels of glutamate were found in SNr and GP of normal rats after DBS of the STN with intracerebral microdialysis (Windels et al, 2003). This effect depended strongly on the frequency of stimulation with a maximum increase of glutamate in the GP and SNr at 130 Hz, weaker increases at either 60 or 350 Hz and no effect at 10 Hz being concordant with the well-known frequency dependence of the clinical effect of DBS of the STN in humans.…”

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.…”

“…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.…”

“…Neurochemical studies support this claim, showing that low-frequency stimulation does not lead to the neurochemical and molecular changes seen with HFS. 52,79 However, not all nuclei or clinical indications require stimulation at frequencies greater than 100 Hz. DBS in the pedunculopontine nucleus (PPN), for example, is most effective at stimulation frequencies between 20 Hz and 60 Hz.…”

Mechanisms of Deep Brain Stimulation in Movement Disorders as Revealed by Changes in Stimulus Frequency

“…Furthermore, glutamate levels in healthy rats increased in GP and SNr as a function of STN DBS frequency up to a plateau at 130 Hz. 40 The increase in glutamate levels was maintained during DBS at frequencies as high as 350 Hz, but was slightly lower than at 130 Hz DBS, indicating that STN neurons released additional glutamate during high-frequency DBS. These data indicate that stimulated activity in the efferent axons of the stimulated nucleus is indeed propagated to downstream nuclei.…”