Alterations in primary motor cortex neurotransmission and gene expression in hemi-parkinsonian rats with drug-induced dyskinesia.

Abstract

Treatment of Parkinson's disease (PD) with dopamine replacement relieves symptoms of poverty of movement, but often causes drug-induced dyskinesias. Accumulating clinical and pre-clinical evidence suggests that the primary motor cortex (M1) is involved in the pathophysiology of PD and that modulating cortical activity may be a therapeutic target in PD and dyskinesia. However, surprisingly little is known about how M1 neurotransmitter tone or gene expression is altered in PD, dyskinesia or associated animal models. The present study utilized the rat unilateral 6-hydroxydopamine (6-OHDA) model of PD/dyskinesia to characterize structural and functional changes taking place in M1 monoamine innervation and gene expression. 6-OHDA caused dopamine pathology in M1, although the lesion was less severe than in the striatum. Rats with 6-OHDA lesions showed a PD motor impairment and developed dyskinesia when given L-DOPA or the D1 receptor agonist, SKF81297. M1 expression of two immediate-early genes (c-Fos and ARC) was strongly enhanced by either L-DOPA or SKF81297. At the same time, expression of genes specifically involved in glutamate and GABA signaling were either modestly affected or unchanged by lesion and/or treatment. We conclude that M1 neurotransmission and signal transduction in the rat 6-OHDA model of PD/dyskinesia mirror features of human PD, supporting the utility of the model to study M1 dysfunction in PD and the elucidation of novel pathophysiological mechanisms and therapeutic targets.

• Authors: D Lindenbach, M M Conti, C Y Ostock, K B Dupre, C Bishop
• Journal: Neuroscience (Neuroscience) Vol. 310 Pg. 12-26 (Dec 03 2015) ISSN: 1873-7544 [Electronic] United States
• PMID: 26363150 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.

Chemical References

• Benzazepines
• Dopamine Agents
• Proto-Oncogene Proteins c-fos
• Levodopa
• SK&F 81297
• Oxidopamine

Topics

• AIDS-Related Complex (genetics, metabolism)
• Animals
• Benzazepines (adverse effects)
• Disease Models, Animal
• Dopamine Agents (adverse effects)
• Dyskinesia, Drug-Induced (etiology, pathology)
• Functional Laterality (drug effects)
• Gene Expression (drug effects, physiology)
• Levodopa (therapeutic use)
• Male
• Medial Forebrain Bundle (injuries)
• Motor Cortex (metabolism)
• Oxidopamine (toxicity)
• Parkinsonian Disorders (chemically induced, drug therapy)
• Proto-Oncogene Proteins c-fos (genetics, metabolism)
• Rats
• Rats, Sprague-Dawley
• Severity of Illness Index
• Synaptic Transmission (drug effects, physiology)