Contribution of decreased serotonin release to the antidyskinetic effects of deep brain stimulation in a rodent model of tardive dyskinesia: comparison of the subthalamic and entopeduncular nuclei.
Mechanisms whereby deep brain stimulation (DBS) of the subthalamic nucleus (STN) or internal globus pallidus (GPi) reduces dyskinesias remain largely unknown. Using vacuous chewing movements (VCMs) induced by chronic haloperidol as a model of tardive dyskinesia (TD) in rats, we confirmed the antidyskinetic effects of DBS applied to the STN or entopeduncular nucleus (EPN, the rodent homolog of the GPi). We conducted a series of experiments to investigate the role of serotonin (5-HT) in these effects. We found that neurotoxic lesions of the dorsal raphe nuclei (DRN) significantly decreased HAL-induced VCMs. Acute 8-OH-DPAT administration, under conditions known to suppress raphe neuronal firing, also reduced VCMs. Immediate early gene mapping using zif268 in situ hybridization revealed that STN-DBS inhibited activity of DRN and MRN neurons. Microdialysis experiments indicated that STN-DBS decreased 5-HT release in the dorsolateral caudate-putamen, an area implicated in the etiology of HAL-induced VCMs. DBS applied to the EPN also suppressed VCMs but did not alter 5-HT release or raphe neuron activation. While these findings suggested a role for decreased 5-HT release in the mechanisms of STN DBS, further microdialysis experiments showed that when the 5-HT lowering effects of STN DBS were prevented by pretreatment with fluoxetine or fenfluramine, the ability of DBS to suppress VCMs remained unaltered. These results suggest that EPN- and STN-DBS have different effects on the 5-HT system. While decreasing 5-HT function is sufficient to suppress HAL-induced VCMs, 5-HT decrease is not necessary for the beneficial motor effects of DBS in this model.
Department of Pharmacology and Toxicology, Toronto Western Hospital, University of Toronto, Ontario M5T 1R8, Canada.
Meaghan C
MC
Creed
Clement
C
Hamani
Alanna
A
Bridgman
Paul J
PJ
Fletcher
José N
JN
Nobrega
D015116:5,7-Dihydroxytryptamine / Q000633:toxicity; D000662:Amphetamines / Q000627:therapeutic use; D000704:Analysis of Variance; D000818:Animals; D014150:Antipsychotic Agents / Q000633:toxicity; D001345:Autoradiography; D001596:Benzylamines / Q000493:pharmacokinetics; D002247:Carbon Isotopes / Q000493:pharmacokinetics; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D046690:Deep Brain Stimulation / Q000379:methods*; D004195:Disease Models, Animal; D055664:Electrochemical Techniques; D020392:Entopeduncular Nucleus / Q000502:physiology*; D005106:Exploratory Behavior / Q000187:drug effects / Q000502:physiology; D005473:Fluoxetine / Q000627:therapeutic use; D006220:Haloperidol / Q000633:toxicity; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D008297:Male; D008409:Mastication / Q000187:drug effects / Q000502:physiology; D017551:Microdialysis; D009069:Movement Disorders / Q000209:etiology / Q000628:therapy*; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000378:metabolism*; D018490:Serotonin Agents / Q000633:toxicity; D017366:Serotonin Receptor Agonists / Q000627:therapeutic use; D017367:Selective Serotonin Reuptake Inhibitors / Q000627:therapeutic use; D020531:Subthalamic Nucleus / Q000502:physiology*
D015116:5,7-Dihydroxytryptamine; D000662:Amphetamines; D014150:Antipsychotic Agents; D001596:Benzylamines; D002247:Carbon Isotopes; D005473:Fluoxetine; D006220:Haloperidol; D006897:Hydroxyindoleacetic Acid; D012701:Serotonin; D018490:Serotonin Agents; D017366:Serotonin Receptor Agonists; D017367:Selective Serotonin Reuptake Inhibitors; C420885:N,N-dimethyl-2-(2-amino-4-cyanophenylthio)benzylamine; C015952:4-iodo-2,5-dimethoxyphenylisopropylamine