Abstract
Using a rat model of hemiparkinsonism, we examined the time-course of D1 agonist, SKF-38393-induced changes in extracellular signaling regulated kinases 1/2 (ERK1/2) phosphorylation in the striatum and substantia nigra (SN). We unilaterally lesioned the rat median forebrain bundle with 6-hydroxydopamine. Dopaminergic lesioned rats were administered with SKF-38393 and perfused at 15, 30, 60, or 120 minutes after the drug. Immunohistochemical analysis of striatum and SN revealed, as expected, a loss of tyrosine hydroxylase and a decrease of substance P in lesioned rats. SKF-38393 induced a robust increase in phospho-ERK1/2 levels in the lesioned striatum, which peaked at 15 min and substantially declined by 120 min. We report for the first time that similar changes were observed in the SN. The time-dependent ERK 1/2 activation in the striatonigral neurons may play a role in the therapeutic and/or side effects such as dyskinesias related to the dopamine agonist treatment for Parkinson’s disease.
Highlights
Dopamine (DA) is involved in many physiological functions including motor control, mood and reward pathways [1,2,3,4,5,6,7]
The present study demonstrates that SKF-38393 induced a robust increase in phospho-extracellular signaling regulated kinases 1/2 (ERK1/2) levels only in the lesioned striatum and substantia nigra (SN) as compared to the intact side
The present study reveals for the first time that increased phosphorylation of ERK1/2 occurs in the SN, suggesting an involvement of the entire striatonigral pathway following DA agonist administration
Summary
Dopamine (DA) is involved in many physiological functions including motor control, mood and reward pathways [1,2,3,4,5,6,7]. The normal functioning of basal ganglia is dependent on the activity of the ‘direct’ (striatonigral) and ‘indirect’ (striatopallidal) output pathways subserved predominantly by the D1 and D2 receptor subtypes [10,11]. Degeneration of the nigrostriatal DA pathway results in an imbalance of the activity of the direct and indirect projection pathways and is thought to be responsible for the movement disorders associated with Parkinson’s disease [3,7,11]. DA agonists restore the normal functions of the direct and indirect pathways when DA is lost [10,11]. One effect of DA-depletion, which is not normalized by DA agonist treatment, is the supersensitive response of direct pathway neurons to D1 agonists [6,12,13,14,15]
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