Effects of cobalt and bicuculline on focal microstimulation of rat pallidal neurons in vivo.
BACKGROUND
Deep brain stimulation (DBS) administered in the basal ganglia is an effective therapy for movement disorders; however, the mechanism(s) of action remain poorly understood.


OBJECTIVE
Because high-frequency electrical stimulation (HFS) preferentially activates fibers, one hypothesis of DBS action is that local release of transmitters from axon terminals underlies the inhibitory effects on spontaneous spiking observed in human intraoperative recordings. We hypothesize that blocking presynaptic release of transmitters will reduce any stimulation-induced effect and blocking of postsynaptic GABA receptors will reduce the inhibitory effect of HFS.


METHODS
We recorded neuronal responses after short HFS trains (2-37 microA, 0.5 seconds, 300 Hz) delivered through the recording electrode or via an adjacent electrode in 42 single globus pallidus (GP) units of anesthetized rats before and after injection of the synaptic blockers cobalt chloride (100 mM) and bicuculline methiodide (2 microg/microL).


RESULTS
Responses to HFS trains were mainly transient ( approximately 350 milliseconds) inhibition of firing, but a late response ( approximately 1-2 seconds) and rebound burst were also found. Excitation was observed in 4 of 43 neurons studied. Neurons with transient inhibition had the response attenuated by 47% after injection of either synaptic blocker, in part supporting the local gamma-aminobutyric acid release hypothesis. Bicuculline methiodide and cobalt attenuated the late response as well as the rebound burst response, but the late inhibitory response was increased by bicuculline methiodide in one case. HFS-induced excitatory responses were not altered by synaptic blockers suggesting direct stimulation of postsynaptic elements of GP neurons.


CONCLUSIONS
The results indicate HFS induces the local inhibition of ongoing activity of the somal region of GP neurons as well as the stimulation of axons and active dendrites. These observations serve to shed light on the mechanism(s) of DBS.
Chin
Gordon D
GD
Department of Physiology, University of Toronto, Ontario, Canada.
Hutchison
William D
WD
D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D001640:Bicuculline / Q000494:pharmacology*; D003035:Cobalt / Q000494:pharmacology*; D046690:Deep Brain Stimulation; D004558:Electric Stimulation / Q000379:methods*; D004594:Electrophysiology; D018756:GABA Antagonists / Q000494:pharmacology*; D005917:Globus Pallidus / Q000166:cytology / Q000502:physiology; D006801:Humans; D008297:Male; D008845:Microinjections; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D014131:Trace Elements / Q000494:pharmacology
D018756:GABA Antagonists; D014131:Trace Elements; D003035:Cobalt; D001640:Bicuculline