High-frequency stimulation of the subthalamic nucleus increases glutamate in the subthalamic nucleus of rats as demonstrated by in vivo enzyme-linked glutamate sensor

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an effective therapy for Parkinson's disease; however, the mechanism whereby DBS ameliorates the symptoms of Parkinson's disease remains an area of intense research. In the present study, we investigated the hypothesis that the neurotransmitter glutamate is released within the STN during high-frequency stimulation (HFS) of the STN. Direct measurements of extracellular glutamate concentration in the STN were made using a dual enzyme-based electrochemical sensor. The studies were carried out in ketamine/xylazine anesthetized rats placed in a Kopf stereotaxic head frame. Various electrical stimulations (100-μs cathodic pulses; 100-3000 μA; 10- to 1000-Hz frequency; 5-s to 60-min stimulus durations) using bipolar stimulating electrodes were delivered to the STN. Stimulation of the STN elevated the concentration of glutamate in the STN. The concentration of glutamate rose quickly during HFS, remained elevated for the duration of stimulation, and descended slowly towards baseline upon cessation of stimulation. Elevation of the extracellular concentration of glutamate in the STN may be an important mechanism whereby DBS in the STN improves the symptoms of Parkinson's disease. Furthermore, our data argue against the hypothesis that DBS works primarily by electrotonic inhibition of the stimulated structure.