Dopamine-mediated gene regulation in models of Parkinson's disease.
The normal functioning of the basal ganglia is dependent on dopamine maintaining a balance between the two major output pathways of the striatum, through the D1 and D2 dopamine receptors, which have opposing effects on these pathways. Lesions of the dopamine system, such as occur in Parkinson's disease (PD), disrupt this balance. Gene regulation studies provide a measure of the cellular and molecular effects of dopamine on striatal neurons in animal models of PD. Dopamine agonists, involving selective or mixed D1 and D2 agonists, such as levodopa, are able to reverse many of the homeostatic changes induced by striatal dopamine depletion. However, following dopamine depletion, a supersensitive responsiveness of D1 striatal neurons to dopamine agonists develops, indicated by the induction of immediate early genes. The molecular and cellular mechanisms underlying the irreversibility of this supersensitive response with long-term dopamine agonist treatments may provide insights into dyskinesias that develop with long-term levodopa therapy in the treatment of PD.
Gerfen
C R
CR
Laboratory of Systems Neuroscience, NIMH, Bethesda, MD 20892-4075, USA.
D000818:Animals; D001923:Brain Chemistry / Q000502:physiology; D003342:Corpus Striatum / Q000166:cytology / Q000503:physiopathology*; D004298:Dopamine / Q000235:genetics*; D015259:Dopamine Agents / Q000009:adverse effects; D015870:Gene Expression / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007980:Levodopa / Q000009:adverse effects; D009474:Neurons / Q000502:physiology*; D010300:Parkinson Disease / Q000188:drug therapy / Q000235:genetics* / Q000503:physiopathology
D015259:Dopamine Agents; D007980:Levodopa; D004298:Dopamine