High‐frequency stimulation of the subthalamic nucleus enhances striatal dopamine release and metabolism in rats

Abstract

High-frequency stimulation of the subthalamic nucleus is believed to exert its main effects via the basal ganglia output structures. Previously, we have shown a concomitant increase in striatal dopamine (DA) metabolites in normal and 6-hydroxydopamine-lesioned rats. The present study was designed to determine whether this increase in striatal DA metabolites reflects enhanced intraneuronal DA turnover or, alternatively, is due to increased DA release with subsequent rapid and efficient reuptake and/or metabolism. Thus, highfrequency stimulation of the subthalamic nucleus was performed in normal rats after inhibition of DA reuptake, metabolism or DA depletion. Extracellular levels of striatal DA and its metabolites were assessed using microdialysis. Our data suggest that subthalamic high-frequency stimulation increases striatal DA release and activates independent striatal DA metabolism. Since such changes could be triggered by modification of either the activity or the gene expression of the rate-limiting enzyme tyrosine hydroxylase, an activity assay and RT-PCR of striatal and nigral samples were performed. Subthalamic stimulation increased striatal tyrosine hydroxylase activity without affecting gene expression. We, therefore, conclude that the application of subthalamic high-frequency stimulation could partially compensate for the DA deficit by inducing increased striatal DA release and metabolism.

Prefrontal Cortical Projections to the Midbrain in Primates: Evidence for a Sparse Connection

“…The cortico-STN projection, which has been a focus of study for motor and premotor cortico-basal ganglia system, is termed the 'hyperdirect' basal ganglia pathway in that impulses reach the basal ganglia output nuclei faster via this route than through the cortico-striatal pathway (Kolomiets et al, 2003). Given that the STN impacts directly on DA cells (Rosales et al, 1994;Meissner et al, 2003), this route (PFC to the STN to the midbrain cells) may represent an alternative in the primate to the direct PFC-VTA/SN pathway observed in other species. In fact, PFC stimulation results in both excitatory and inhibitory responses in the primate SN pars reticulata, which are mediated via the STN and striatum, respectively (Kitano et al, 1998).…”

Neural Circuit Modulation During Deep Brain Stimulation at the Subthalamic Nucleus for Parkinson's Disease: What Have We Learned from Neuroimaging Studies?

“…Specifically, release was maximal at high frequencies ( ‡ 120 Hz) and voltages (7 V, highest tested). The use of a normal animal model weakens the therapeutic relevance of these findings, although microdialysis studies in rats with nigrostriatal lesions have also found increased striatal dopamine release by STN-DBS (Meissner et al, 2002(Meissner et al, , 2003.…”

Real-time simultaneous recording of electrophysiological activities and dopamine overflow in the deep brain nuclei of a non-human primate with Parkinson’s disease using nano-based microelectrode arrays

“…Researchers have hypothesized that the level of DA and its metabolites in the corpus striatum are increased after STN-HFS. 1 Early reports showed that HFS increased major DA metabolic products in the striatum of 6-hydroxydopamine (6-OHDA) lesioned rats 15,16 . This result could explain the immediate improvement after the electrical stimulation.…”