High frequency stimulation of the subthalamic nucleus evokes striatal dopamine release in a large animal model of human DBS neurosurgery

Subthalamic nucleus deep brain stimulation (STN DBS) ameliorates motor symptoms of Parkinson's disease, but the precise mechanism is still unknown. Here, using a large animal (pig) model of human STN DBS neurosurgery, we utilized fast-scan cyclic voltammetry in combination with a carbon-fiber microelectrode (CFM) implanted into the striatum to monitor dopamine release evoked by electrical stimulation at a human DBS electrode (Medtronic 3389) that was stereotactically implanted into the STN using MRI and electrophysiological guidance. STN electrical stimulation elicited a stimulus time-locked increase in striatal dopamine release that was both stimulus intensity- and frequency-dependent. Intensity-dependent (1-7. V) increases in evoked dopamine release exhibited a sigmoidal pattern attaining a plateau between 5 and 7. V of stimulation, while frequency-dependent dopamine release exhibited a linear increase from 60 to 120. Hz and attained a plateau thereafter (120-240. Hz). Unlike previous rodent models of STN DBS, optimal dopamine release in the striatum of the pig was obtained with stimulation frequencies that fell well within the therapeutically effective frequency range of human DBS (120-180. Hz). These results highlight the critical importance of utilizing a large animal model that more closely represents implanted DBS electrode configurations and human neuroanatomy to study neurotransmission evoked by STN DBS. Taken together, these results support a dopamine neuronal activation hypothesis suggesting that STN DBS evokes striatal dopamine release by stimulation of nigrostriatal dopaminergic neurons.