title: Three mechanisms by which striatal denervation causes breakdown of dopamine signaling.
abstract: Progressive loss of nigrostriatal dopamine (DA) neurons is the neuropathological hallmark of Parkinson's disease (PD). Symptoms of the disease can often be treated by DA D2 agonists and thus seem related to disinhibition of the indirect striatal pathway. However, there is no evidence that symptoms arise by low extracellular DA concentration or are associated with reduced D2 receptor binding. Here I provide a theoretical analysis of the pathophysiology and postsynaptic adaptation resulting from striatal DA denervation. I found that progressive denervation may alter DA signaling by three independent mechanisms depending on degree of denervation and macroscopic morphology of the lesion. As long as the remaining innervation stays anatomically coherent, denervation reduces phasic variations in extracellular DA, but the DA tone is not changed. The reduction of phasic signaling can be partially compensated by upregulating postsynaptic signaling cascades. However, changes in DA dynamics evade compensation. With 80-99% denervation, a persistent aberrant signal develops in D2-regulated pathways caused by random fluctuations in tonic DA release. Permanent low DA levels occur in regions completely void of innervation. Simulation of l-dopa therapy reduced the aberrant D2 signal. With a high degree of denervation, l-dopa enhanced another aberrant signal, this time in the D1 pathway. This analysis provides a quantitative, physiologically consistent view of the early and late stages of PD, the effect of main therapeutic medications, and potential side effects. The mechanisms described here may also provide an explanation to currently inexplicable pathological phenomena such as psycho stimulant-induced contraversive rotations in animal models.
authors.affiliation: Department of Neuroscience and Pharmacology, University of Copenhagen, 2200 Copenhagen, Denmark jakobdr@sund.ku.dk.
authors.forename: Jakob K
authors.initials: JK
authors.lastname: Dreyer
mesh_terms: D003198:Computer Simulation; D003342:Corpus Striatum / Q000503:physiopathology* / Q000601:surgery; D003714:Denervation; D004298:Dopamine / Q000378:metabolism*; D059290:Dopaminergic Neurons / Q000378:metabolism*; D006801:Humans; D008959:Models, Neurological; D009433:Neural Inhibition; D010300:Parkinson Disease / Q000503:physiopathology*; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D017448:Receptors, Dopamine D2; D004298:Dopamine
keywords: D2 receptor; Parkinson's disease; compensation; dopamine; supersensitivity