Differential Involvement of D1 and D2 Dopamine Receptors in L-DOPA-Induced Angiogenic Activity in a Rat Model of Parkinson's Disease

Abstract

Angiogenesis occurs in the brains of Parkinson's disease patients, but the effects of dopamine replacement therapy on this process have not been examined. Using rats with 6-hydroxydopamine lesions, we have compared angiogenic responses induced in the basal ganglia by chronic treatment with either L-DOPA, or bromocriptine, or a selective D1 receptor agonist (SKF38393). Moreover, we have asked whether L-DOPA-induced angiogenesis can be blocked by co-treatment with either a D1-or a D2 receptor antagonist (SCH23390 and eticlopride, respectively), or by an inhibitor of extracellular signal-regulated kinases 1 and 2 (ERK1/2) (SL327). L-DOPA, but not bromocriptine, induced dyskinesia, which was associated with endothelial proliferation, upregulation of immature endothelial markers (nestin) and downregulation of endothelial barrier antigen in the striatum and its output structures. At a dose inducing dyskinesia (1.5 mg/kg/day), SKF38393 elicited angiogenic changes similar to L-DOPA. Antagonism of D1-but not D2 class receptors completely suppressed both the development of dyskinesia and the upregulation of angiogenesis markers. In fact, L-DOPA-induced endothelial proliferation was markedly exacerbated by low-dose D2 antagonism (0.01 mg/kg eticlopride). Inhibition of ERK1/2 by SL327 attenuated L-DOPA-induced dyskinesia and completely inhibited all markers of angiogenesis. These results highlight the specific link between treatment-induced dyskinesias and microvascular remodeling in the dopamine-denervated brain. L-DOPA-induced angiogenesis requires stimulation of D1 receptors and activation of ERK1/2, whereas the stimulation of D2 receptors seems to oppose this response.

mTORC1 signaling in Parkinson disease and L-DOPA-induced dyskinesia: A sensitized matter

“…27 The importance of abnormal regulation of ERK in LID is indicated by the observation that, in the mouse, administration of SL327, a MEK inhibitor which suppresses ERK phosphorylation, reduces dyskinesia. 27 Similar results have been recently obtained in the rat, 32 where dyskinesia is also attenuated by lovastatin, a drug which reduces ERK activation via inhibition of the small GTPase, Ras. 33 ERK signaling has been intensively studied for its ability to control gene expression, via regulation of several nuclear effectors.…”

Controlled-release levodopa methyl ester/benserazide-loaded nanoparticles ameliorate levodopa-induced dyskinesia in rats

“…[13][14][15] The increases in ERK1/2 activation and ∆fosB expression after chronic treatment appear to be specific to the supersensitive response to levodopa induced by the dopaminergic lesion because neither acute nor chronic levodopa treatment activates ERK1/2 phosphorylation or increases ∆fosB expression in the dopamine-intact striatum. 16,17 Phosphorylation and activation of ERK1/2 and subsequent translocation to Figure 8 Effect of administration of LDME/benserazide-loaded nanoparticles on levels of p-DARPP-32, p-ERK1/2, and ∆fosB.…”

Different Modulation of Rps6 Phosphorylation by Risperidone in Striatal Cells Sub Populations: Involvement of the mTOR Pathway in Antipsychotic-Induced Extrapyramidal Symptoms in Mice

“…Signaling patterns differ in DRD1 and DRD2 neurons, in other words, there is complete mechanistic segregation between the striatonigral and striatopallidal circuits within the striatum in response to pharmacological stimuli [34,35]. In fact, dopamine receptors encoded in the Drd1a and Drd2 genes have been identified for association with haloperidol-induced tardive dyskinesia in mice [24,36].…”