title: The Role of Primary Motor Cortex (M1) Glutamate and GABA Signaling in l-DOPA-Induced Dyskinesia in Parkinsonian Rats.
abstract: Long-term treatment of Parkinson's disease with l-DOPA almost always leads to the development of involuntary movements termed l-DOPA-induced dyskinesia. Whereas hyperdopaminergic signaling in the basal ganglia is thought to cause dyskinesia, alterations in primary motor cortex (M1) activity are also prominent during dyskinesia, suggesting that the cortex may represent a therapeutic target. The present study used the rat unilateral 6-hydroxydopamine lesion model of Parkinson's disease to characterize in vivo changes in GABA and glutamate neurotransmission within M1 and determine their contribution to behavioral output. 6-Hydroxydopamine lesion led to parkinsonian motor impairment that was partially reversed by l-DOPA. Among sham-lesioned rats, l-DOPA did not change glutamate or GABA efflux. Likewise, 6-hydroxydopamine lesion did not impact GABA or glutamate among rats chronically treated with saline. However, we observed an interaction of lesion and treatment whereby, among lesioned rats, l-DOPA given acutely (1 d) or chronically (14-16 d) reduced glutamate efflux and enhanced GABA efflux. Site-specific microinjections into M1 demonstrated that l-DOPA-induced dyskinesia was reduced by M1 infusion of a D1 antagonist, an AMPA antagonist, or a GABAA agonist. Overall, the present study demonstrates that l-DOPA-induced dyskinesia is associated with increased M1 inhibition and that exogenously enhancing M1 inhibition may attenuate dyskinesia, findings that are in agreement with functional imaging and transcranial magnetic stimulation studies in human Parkinson's disease patients. Together, our study suggests that increasing M1 inhibitory tone is an endogenous compensatory response designed to limit dyskinesia severity and that potentiating this response is a viable therapeutic strategy.
  
  
  
  Most Parkinson's disease patients will receive l-DOPA and eventually develop hyperkinetic involuntary movements termed dyskinesia. Such symptoms can be as debilitating as the disease itself. Although dyskinesia is associated with dynamic changes in primary motor cortex physiology, to date, there are no published studies investigating in vivo neurotransmitter release in M1 during dyskinesia. In parkinsonian rats, l-DOPA administration reduced M1 glutamate efflux and enhanced GABA efflux, coincident with the emergence of dyskinetic behaviors. Dyskinesia could be reduced by local M1 modulation of D1, AMPA, and GABAA receptors, providing preclinical support for the notion that exogenously blunting M1 signaling (pharmacologically or with cortical stimulation) is a therapeutic approach to the treatment of debilitating dyskinesias.
authors.affiliation: Behavioral Neuroscience Program, Department of Psychology, Binghamton University, State University of New York, Binghamton, New York 13901 dlinden1@binghamton.edu cbishop@binghamton.edu.
authors.forename: David
authors.identifier: 0000-0002-9422-697X
authors.initials: D
authors.lastname: Lindenbach
authors.affiliation: Behavioral Neuroscience Program, Department of Psychology, Binghamton University, State University of New York, Binghamton, New York 13901.
authors.forename: Melissa M
authors.initials: MM
authors.lastname: Conti
authors.affiliation: Behavioral Neuroscience Program, Department of Psychology, Binghamton University, State University of New York, Binghamton, New York 13901.
authors.forename: Corinne Y
authors.initials: CY
authors.lastname: Ostock
authors.affiliation: Behavioral Neuroscience Program, Department of Psychology, Binghamton University, State University of New York, Binghamton, New York 13901.
authors.forename: Jessica A
authors.initials: JA
authors.lastname: George
authors.affiliation: Behavioral Neuroscience Program, Department of Psychology, Binghamton University, State University of New York, Binghamton, New York 13901.
authors.forename: Adam A
authors.initials: AA
authors.lastname: Goldenberg
authors.affiliation: Behavioral Neuroscience Program, Department of Psychology, Binghamton University, State University of New York, Binghamton, New York 13901.
authors.forename: Mitchell
authors.initials: M
authors.lastname: Melikhov-Sosin
authors.affiliation: Behavioral Neuroscience Program, Department of Psychology, Binghamton University, State University of New York, Binghamton, New York 13901.
authors.forename: Emily E
authors.initials: EE
authors.lastname: Nuss
authors.affiliation: Behavioral Neuroscience Program, Department of Psychology, Binghamton University, State University of New York, Binghamton, New York 13901 dlinden1@binghamton.edu cbishop@binghamton.edu.
authors.forename: Christopher
authors.identifier: 0000-0003-4623-1085
authors.initials: C
authors.lastname: Bishop
mesh_terms: D000818:Animals; D000978:Antiparkinson Agents / Q000009:adverse effects; D003342:Corpus Striatum / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D018683:Excitatory Amino Acid Agents / Q000494:pharmacology; D018682:GABA Agents / Q000494:pharmacology; D018698:Glutamic Acid / Q000378:metabolism*; D007980:Levodopa / Q000009:adverse effects; D008297:Male; D009044:Motor Cortex / Q000187:drug effects / Q000378:metabolism*; D009068:Movement / Q000187:drug effects; D016627:Oxidopamine / Q000633:toxicity; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000188:drug therapy; D011597:Psychomotor Performance / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects*; D013565:Sympatholytics / Q000633:toxicity; D000071057:Tardive Dyskinesia / Q000139:chemically induced / Q000473:pathology*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D000978:Antiparkinson Agents; D018683:Excitatory Amino Acid Agents; D018682:GABA Agents; D013565:Sympatholytics; D018698:Glutamic Acid; D007980:Levodopa; D005680:gamma-Aminobutyric Acid; D016627:Oxidopamine
keywords: GABA; Parkinson's disease; dopamine; glutamate; l-DOPA; motor cortex