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Dopamine Receptors and the Treatment of Parkinson’s Disease

Part of the The Receptors book series (REC)

Abstract

Parkinson’s disease is a devastating disorder caused by progressive degeneration of dopaminergic neurons in the substantia nigra and the consequent loss of dopamine in the striatum. Dopamine replacement therapy with the dopamine precursor levodopa (l-DOPA), introduced in the 1960s, remains the most effective treatment. Unfortunately, l-DOPA, upon long-term administration, gradually loses its efficacy and eventually leads to severe motor complications, including dyskinesia. The data from numerous studies on Parkinson’s patients and animal models of the disease show a complex pattern of changes in multiple signaling pathways in the striatum induced by dopamine depletion. These include modulation of the expression and activity of several subtypes of dopamine receptors, G proteins, effectors, multiple protein kinases, components of the machinery for desensitization and trafficking of G protein-coupled receptors, ionotropic glutamate receptors, and transcription factors. Dopamine replacement therapy reverses many of these changes. However, select signaling effects are exacerbated and/or induced de novo by chronic treatment with l-DOPA. The l-DOPA-induced dyskinesia appears closely associated with selective increases in the activity of specific D1 receptor-dependent pathways. The contribution of D2 and D3 receptor-mediated signaling to dyskinesia development remains largely unexplored. The mechanisms underlying the further enhancement by l-DOPA of signaling pathways already made supersensitive by dopamine depletion need to be elucidated. The recently introduced long-lived dopamine agonists cause less dyskinesia than l-DOPA but are also less efficacious as antiparkinsonian agents. The clinically used DA agonists, which target D2-like receptors and often show preference for the D3 over D2 subtype, in addition to their antiparkinsonian action, may protect surviving dopaminergic neurons. Continuous delivery of l-DOPA or dopamine agonists, which mimics the physiological tonic stimulation of dopamine receptors, holds the promise of providing therapeutic benefits with minimal side effects. A much better understanding of the molecular processes underlying the therapeutic action of dopaminergic drugs and the development of dyskinesia is necessary in order to modify existing treatments and/or devise new approaches to maximize the beneficial effects of dopamine replacement and minimize the side effects.

Keywords

  • Parkinson’s disease
  • l-DOPA
  • Dyskinesia
  • Motor complications
  • Sensitization
  • Receptor supersensitivity

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Gurevich, E.V., Gurevich, V.V. (2010). Dopamine Receptors and the Treatment of Parkinson’s Disease. In: Neve, K. (eds) The Dopamine Receptors. The Receptors. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-60327-333-6_18

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