High frequency stimulation of the entopeduncular nucleus has no effect on striatal dopaminergic transmission

Abstract

High frequency stimulation (HFS) of the subthalamic nucleus (STN) is thought to be superior to stimulation of the internal pallidum (GPi) in alleviating symptoms of Parkinson’s disease (PD). However, preliminary controlled studies comparing the effectiveness of both targets have not found significant differences in the improvement of parkinsonian symptoms, but have shown that STN stimulation allows a dramatic decrease in dopaminergic medication. We have previously shown that STN-HFS increases striatal extracellular dopamine (DA) metabolites, but not DA, in both naive and 6-hydroxydopamine (6-OHDA)-lesioned rats, whereas stimulation of the entopeduncular nucleus (EP), the rodent equivalent of the internal pallidum, does not affect DA or metabolite levels. Intriguingly, STN-HFS increases striatal DA release after inhibition of DA reuptake or metabolism, suggesting that this observation may have been obscured in non-drug treated animals by rapid and effective DA reuptake. Since STN-HFS further enhances DA metabolism after DA reuptake inhibition or depletion it has been proposed that STN-HFS increases both, striatal DA release and metabolism, independently. Therefore, the present study assesses the impact of EP-HFS on striatal DA release and metabolism in normal rats after inhibition of DA reuptake or metabolism, using microdialysis. In summary, our data demonstrate that, contrary to STN stimulation, EP-HFS has no effect on striatal DA release and metabolism. Thus, the present study provides a partial explanation for the reported clinical differences, and experimental evidence for differential mechanisms of action between HFS of the internal pallidum and the STN, that are most likely related to differences in functional anatomy.

Introduction

High frequency stimulation (HFS), also known as deep brain stimulation, of the internal pallidum (GPi) and the subthalamic nucleus (STN) is an established therapeutic approach for the treatment of major motor symptoms and long-term levodopa-induced complications in Parkinson’s disease (PD) (Benabid et al., 1998). Despite growing clinical experience with HFS, the exact mechanisms of action remain unknown. Based on clinical observations, STN-HFS is regarded to be superior to GPi-HFS (Houeto et al., 2000, Krack et al., 1998). However, preliminary controlled studies comparing the effectiveness of GPi- and STN-HFS have found only few or no significant differences in the improvement of PD motor symptoms except for a significant decrease of dopaminergic medication in patients receiving STN-HFS (Brown et al., 1999, Burchiel et al., 1999, Nutt et al., 2001, Robertson et al., 2001). All these studies, however, were not powered to detect clinical differences between GPi- and STN-HFS because of the small number of patients included.

Although restricted by the temporal resolution, indirect techniques such as microdialysis that allow sampling during stimulation are suitable to detect HFS related changes in neuronal activity, since direct electrophysiological recordings are still limited by the stimulation artifact. Previously, using microdialysis, we have shown that STN-HFS increases extracellular striatal dopamine (DA) metabolites, but not DA, in both naive and 6-hydroxydopamine (6-OHDA)-lesioned rats (Meissner et al., 2001, Paul et al., 2000). In contrast, HFS of the entopeduncular nucleus (EP, in rodents corresponds to primate GPi) neither affects DA metabolism nor release using the same experimental design (Meissner et al., 2000). In order to understand these results more clearly, we have recently shown that STN-HFS increases striatal DA release after inhibition of DA reuptake or metabolism suggesting that increased DA release may have been obscured in non-drug treated animals by rapid and effective DA reuptake and metabolism (Meissner et al., 2003). Since STN-HFS further enhances DA metabolism after DA reuptake inhibition or depletion, it has been proposed that STN-HFS increases both striatal DA release and metabolism independently (Meissner et al., 2003).

Thus, we hypothesize that, in contrast to STN stimulation, EP-HFS has no effect on striatal DA release and metabolism, suggesting the existence of differential mechanisms of action of GPi- and STN-HFS. In order to further test this hypothesis, extracellular concentrations of striatal DA and its metabolites were assessed before, during and after EP-HFS, using microdialysis and HPLC with electrochemical detection, while DA reuptake and metabolism were inhibited with the dopamine reuptake inhibitor, nomifensine, or the monoamine oxidase (MAO, EC 1.4.3.4) inhibitor, pargyline, in normal rats.