Dopamine Receptors and the Treatment of Parkinson's Disease

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