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L-DOPA regulates glutamate decarboxylases mRNA levels in MPTP-treated monkeys
J J Soghomonian1, S Pedneault, P J Blanchet
1Centre de Recherche en Neurobiologie, Université Laval, Hôpital de l'Enfant-Jésus, Quebec, Canada.
Abstract:
The effect of dopaminergic denervation, alone or followed by chronic intermittent L-DOPA administration, on the levels of mRNAs encoding for the two isoforms of the GABA-synthesizing enzyme, glutamate decarboxylase (GAD65 and GAD67), were measured by in-situ hybridization in the caudate and putamen of macaque monkeys. When compared to control monkeys, the level of GAD67 mRNA was increased in the putamen and caudate of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys. On the other hand, GAD65 mRNA labeling in MPTP-treated monkeys was not significantly different from the controls. In MPTP-treated monkeys that received L-DOPA, a significant increase in both GAD67 and GAD65 mRNA levels was measured in the putamen when compared to control or MPTP-treated monkeys. The results suggest that the dyskinetic effect of L-DOPA is paralleled by an increased GABAergic activity in the striatum.
Insights
Dopamine-depleted monkeys showed increased GAD67 mRNA. L-DOPA treatment further increased both GAD65 and GAD67 mRNA, suggesting enhanced GABAergic activity contributes to L-DOPA-induced dyskinesia.
Area of Science:
- Neuroscience
- Molecular Biology
- Pharmacology
Background:
- Dopaminergic denervation, a hallmark of Parkinson's disease, alters neurotransmitter systems.
- Glutamate decarboxylase (GAD) synthesizes GABA, the primary inhibitory neurotransmitter in the brain.
- L-DOPA is a primary treatment for Parkinson's but can cause dyskinesia.
Purpose of the Study:
- To investigate the impact of dopaminergic denervation and L-DOPA treatment on GABAergic markers.
- To quantify changes in glutamate decarboxylase (GAD65 and GAD67) mRNA levels in the striatum.
Main Methods:
- Used in-situ hybridization to measure GAD65 and GAD67 mRNA levels.
- Studied macaque monkeys with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic denervation.
- Administered chronic intermittent L-DOPA to a subset of MPTP-treated monkeys.
Main Results:
- MPTP treatment increased GAD67 mRNA in the caudate and putamen compared to controls.
- GAD65 mRNA levels were unchanged in MPTP-treated monkeys.
- L-DOPA administration significantly elevated both GAD65 and GAD67 mRNA in the putamen.
Conclusions:
- Dopaminergic denervation upregulates GAD67 mRNA in the striatum.
- L-DOPA treatment further increases GAD mRNA levels, indicating enhanced GABAergic activity.
- Increased striatal GABAergic activity may underlie L-DOPA-induced dyskinesia.