Deep-brain stimulation at high frequencies (HFS) directed to the subthalamic nucleus (STN) is used increasingly to treat patients with
Parkinson's disease. However, the mechanism of action by which HFS of the STN achieves its
therapeutic effects remains unresolved. Insofar as lesions of the STN have similar therapeutic benefit, a favored hypothesis is that HFS acts by suppressing neural activity in the STN. The purpose of the present study was to exploit prior observations that exposure to
ether anesthesia in a rodent model evokes c-fos expression (a marker of neural activation) in the STN and its efferent structures, the globus pallidus, entopeduncular nucleus and substantia nigra. We showed first that exposure to
ether induced a profound oscillatory pattern of neural activity in the STN and SNr, which could explain the marked induction of c-fos immunoreactivity in these structures. Secondly, inhibition of the STN by local
injections of the
GABA agonist,
muscimol, suppressed
ether-evoked c-fos expression in all target structures. This showed that excitation of target structures in the
ether model originated, at least in part, from the STN. Thirdly, and contrary to expectation, HFS of the STN increased further the expression of c-fos in the STN target structures of animals treated with
ether. Finally, we demonstrated, in the absence of
ether treatment, that HFS and chemical stimulation of the STN with local
injections of
kainic acid both induced c-fos expression in the globus pallidus, entopeduncular nucleus and substantia nigra. Together these results suggest that the principal action of STN stimulation at high frequencies is to excite rather than inhibit its efferent targets. Given that
Parkinsonism has been associated with increased levels of inhibitory output activity from the basal ganglia, it is unlikely that excitation of output structures revealed in this study provides a basis for
deep-brain stimulation's therapeutic action.