The Time Course of D1 Agonist Induced Striatonigral ERK1/2 Signaling in a Rat Model of Parkinson’s Disease

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.

GABA Attenuates L-DOPA-Induced Striatal and Nigral ERK1/2 Signaling in a Rat Model of Parkinson’s Disease

“…Furthermore, D1 receptor supersensitivity associated with PD is characterized by changes in synaptic plasticity [9,52] and gene expression [11,53], such as increased expression of D1 receptors at the plasma membrane [21,54,55] and a switch in the regulation of the ERK1/2 signaling pathway [6]. Other evidence indicates that D1 receptor agonists such as SKF-38393 can induce phospho-ERK1/2 levels in the striatum [6,8,22,28,52]. Blockade of D1 receptors with D1-antagonist, SCH-23390 can block L-DOPA-induced ERK1/2 phosphorylation in neonatal (bilateral dopaminergic lesion) [22] and adult (unilateral dopaminergic lesion) models of PD [24,[56][57], indicating that activation of D1 receptors induces effects in the striatum via the ERK1/2 signaling cascade.…”

“…This phenomenon has been linked to the development of motor side effects in reports involving both hemiparkinsonian rodents [24][25][26] and non-human primates [16][17]21,27]. Moreno and Sivam (2012) recently reported that the D1 agonist, SKF-38393 increased phospho-ERK1/2 levels in the striatum and in the substantia nigra (SN), and both responses were blocked by D1 antagonist SCH-23390 [28], further supporting the link between D1 receptor supersensitivity and ERK1/2 signaling in the striatum and SN.…”

“…Lesions of the nigrostriatal DA pathway were made unilaterally in the right median forebrain bundle (MFB) as previously described [28] by infusion of 9 µg of freebase 6-OHDA (Research Biochemicals, Inc.) in ascorbic acid (4 μl, 0.1% in saline, Sigma-Aldrich, Inc.) using ketamine HCl/xylazine HCl solution (80 mg/kg, i.p., Sigma-Aldrich, Inc.) for anesthesia. The stereotaxic coordinates of the MFB relative to the bregma were, A: 4.4, L: 1.2, V: 7.8, and the I-bar was set at −2.5.…”

“…The extent of the unilateral 6-OHDA lesion was assessed by apomorphine-induced rotation test as previously described [28]. Two weeks post-surgery, an apomorphineinduced rotation test (apomorphine HCl, 0.1 mg/kg, i.p., Sigma-Aldrich, Inc., in 0.1% sodium bisulphite solution, Sigma-Aldrich, Inc., in saline) was applied.…”

“…Sunken brains were removed and frozen, and sections through the striatum-and SN-containing regions were cut (30 µm) coronally on a sliding microtome. Sections were collected into the sucrose solution for storage until processed according to the general protocol of [22], as modified previously [28]. Free-floating brain tissue sections were rinsed in phosphate-buffered saline (PBS) (0.15 M NaCl, 0.1 M sodium phosphate, pH 7.4), and subsequently incubated in 0.3% H 2 O 2 .…”