A combined in vivo neurochemical and electrophysiological analysis of the effect of high-frequency stimulation of the subthalamic nucleus on 5-HT transmission

Movement disability in advanced Parkinson's disease (PD) can be treated by high frequency stimulation (HFS) of the subthalamic nucleus (STN) but some patients experience psychiatric side-effects including depression, which is strongly linked to decreases in 5-hydroxytryptamine (5-HT). The current study investigated the effect of bilateral STN HFS on extracellular 5-HT in brain regions of anesthetized and freely moving rats as measured with microdialysis. Parallel in vivo electrophysiological experiments allowed a correlation of changes in extracellular 5-HT with the firing of 5-HT neurons. Bilateral STN HFS decreased (by up to 25%) extracellular levels of 5-HT in both striatum and medial prefrontal cortex of anesthetized rats. STN HFS also decreased extracellular 5-HT in the medial prefrontal cortex of freely moving rats. This decrease in extracellular 5-HT persisted after turning off the stimulation, and was present in dopamine-denervated rats. As with changes in extracellular 5-HT, in anesthetized rats STN HFS evoked a decrease in the in vivo firing of midbrain raphe 5-HT neurons that also persisted after cessation of stimulation. These data provide neurochemical evidence for an inhibition of 5-HT neurotransmission by STN HFS, which may contribute to its psychiatric side effects and guide therapeutic options. ► Mood changes are side effects of deep brain stimulation of the subthalamic nucleus. ► This study shows that STN DBS in a rat model decreased 5-HT neurotransmission. ► STN DBS inhibited 5-HT release and 5-HT neuronal activity. ► Inhibited 5-HT neurotransmission may contribute to mood changes elicited by STN DBS.