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Differential regulation of striatal preproenkephalin mRNA by D1 and D2 dopamine receptors
1Department of Neuroscience, University of Virginia Health Sciences Center, Charlottesville 22908.
Abstract:
The effect of administration of subtype selective dopamine (DA) agonists on the 6-hydroxydopamine (6-OHDA) lesion-induced increase of striatal preproenkephalin (PPE) mRNA was examined by dot-blot hybridization. Eight days following a unilateral 6-OHDA lesion of the substantia nigra pars compacta (SNc), PPE mRNA levels in the ipsilateral striatum were increased approximately two-fold. Administration of the D2 DA agonist, quinpirole, dose-dependently attenuated the 6-OHDA lesion-induced increase in striatal PPE mRNA. The effect of quinpirole was blocked by coadministration of the D2 DA antagonist eticlopride. In contrast, administration of the D1 DA agonist, SKF 38393, either dose-dependently augmented or had no effect on the 6-OHDA lesion-induced increase in striatal PPE mRNA. In the contralateral striatum, administration of quinpirole decreased PPE mRNA, while administration of SKF 38393 increased PPE mRNA compared to sham lesioned control levels. These data suggest the action of DA at D1 and D2 DA receptors differentially regulates striatal PPE mRNA levels and the apparent inhibition of ENK biosynthesis by DA is mediated via an interaction with D2 DA receptors.
Insights
Dopamine (DA) agonists targeting D2 receptors, like quinpirole, reduce increased striatal preproenkephalin (PPE) mRNA after 6-hydroxydopamine (6-OHDA) lesions. D1 agonists have varied effects, suggesting differential regulation of PPE mRNA by dopamine receptor subtypes.
Area of Science:
- Neuroscience
- Molecular Biology
- Pharmacology
Background:
- The 6-hydroxydopamine (6-OHDA) model is used to study dopaminergic neurodegeneration.
- Striatal preproenkephalin (PPE) mRNA levels are altered following dopaminergic lesions.
- Dopamine (DA) receptors, specifically D1 and D2 subtypes, play crucial roles in striatal function.
Purpose of the Study:
- To investigate the differential effects of D1 and D2 dopamine receptor agonists on striatal PPE mRNA levels in a 6-OHDA lesioned rat model.
- To elucidate the role of specific dopamine receptor subtypes in regulating enkephalin biosynthesis following dopaminergic neurodegeneration.
Main Methods:
- Unilateral 6-hydroxydopamine (6-OHDA) lesions of the substantia nigra pars compacta (SNc) in rats.
- Administration of subtype-selective dopamine (DA) agonists (D1: SKF 38393; D2: quinpirole) and antagonists (D2: eticlopride).
- Quantification of striatal preproenkephalin (PPE) mRNA levels using dot-blot hybridization.
Main Results:
- 6-OHDA lesions significantly increased ipsilateral striatal PPE mRNA levels.
- The D2 agonist quinpirole dose-dependently attenuated the 6-OHDA-induced increase in PPE mRNA, an effect blocked by the D2 antagonist eticlopride.
- The D1 agonist SKF 38393 showed variable effects, either augmenting or having no significant effect on the lesion-induced increase in PPE mRNA.
- In the contralateral striatum, quinpirole decreased PPE mRNA, while SKF 38393 increased it compared to controls.
Conclusions:
- Dopamine (DA) acting at D1 and D2 receptors differentially regulates striatal PPE mRNA levels.
- The observed inhibition of enkephalin (ENK) biosynthesis by DA appears to be mediated through D2 dopamine receptors.
- These findings highlight the distinct roles of dopamine receptor subtypes in modulating striatal gene expression following dopaminergic damage.