Abstract
Parkinson’s disease is a common neurodegenerative disorder caused by the degeneration of midbrain substantia nigra dopaminergic neurons that project to the striatum. Despite extensive investigation aimed at finding new therapeutic approaches, the dopamine precursor molecule, 3,4-dihydroxyphenyl-l-alanine (l-DOPA), remains the most effective and commonly used treatment. However, chronic treatment and disease progression lead to changes in the brain’s response to l-DOPA, resulting in decreased therapeutic effect and the appearance of dyskinesias. l-DOPA-induced dyskinesia (LID) interferes significantly with normal motor activity and persists unless l-DOPA dosages are reduced to below therapeutic levels. Thus, controlling LID is one of the major challenges in Parkinson’s disease therapy. LID is the result of intermittent stimulation of supersensitive D1 dopamine receptors located in the very severely denervated striatal neurons. Through increased coupling to Gαolf, resulting in greater stimulation of adenylyl-cyclase, D1 receptors phosphorylate DARPP-32, and other protein kinase A targets. Moreover, D1 receptor stimulation activates extracellular signal-regulated kinase and triggers a signaling pathway involving mammalian target for rapamycin and modifications of histones that results in changes in translation, chromatin modification, and gene transcription. In turn, sensitization of D1 receptor signaling causes a widespread increase in the metabolic response to D1 agonists and changes in the activity of basal ganglia neurons that correlate with the severity of LID. Importantly, different studies suggest that dyskinesias may share mechanisms with drug abuse and long term memory involving D1 receptor activation. Here we review evidence implicating D1 receptor signaling in the genesis of LID, analyze mechanisms that may translate enhanced D1 signaling into dyskinetic movements, and discuss the possibility that the mechanisms underlying LID are not unique to the Parkinson’s disease brain.
Highlights
After the recognition that l-DOPA in combination with a peripheral decarboxylase inhibitor has a dramatic therapeutic effect in Parkinson’s disease, it became clear that the treatment was associated with major adverse effects like the appearance of severely incapacitating abnormal involuntary movements (Cotzias et al, 1969; Papavasiliou et al, 1972)
D1 receptor stimulation activates extracellular signal-regulated kinase and triggers a signaling pathway involving mammalian target for rapamycin and modifications of histones that results in changes in translation, chromatin modification, and gene transcription
The principal candidates for the mechanism underlying l-DOPA-induced dyskinesia (LID) are long term functional and structural changes induced in the dopamine-depleted striatum by dopamine-regulated signaling cascades (Jenner, 2008; Voon et al, 2009; Cenci and Konradi, 2010)
Summary
After the recognition that l-DOPA in combination with a peripheral decarboxylase inhibitor has a dramatic therapeutic effect in Parkinson’s disease, it became clear that the treatment was associated with major adverse effects like the appearance of severely incapacitating abnormal involuntary movements (Cotzias et al, 1969; Papavasiliou et al, 1972). LID IS ASSOCIATED WITH CHANGES IN D1 RECEPTOR SIGNALING IN THE DOPAMINE-DEPLETED STRIATUM Early studies showing that deletion of the D1R gene blocks control of striatal prodynorphin expression and motor behavior by cocaine and amphetamine called attention to D1R signaling in behavioral sensitization to psychostimulants (Moratalla et al, 1996a).
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