Dopaminergic modulation by quercetin: In silico and in vivo evidence using Caenorhabditis elegans as a model

Quercetin is a flavonol widely distributed in plants and has various described biological functions. Several studies have reported on its ability to restore neuronal function in a wide variety of disease models, including animal models of neurodegenerative disorders such as Parkinson's disease. Quercetin per se can act as a neuroprotector/neuromodulator, especially in diseases related to impaired dopaminergic neurotransmission. However, little is known about how quercetin interacts with the dopaminergic machinery. Here we employed the nematode Caenorhabditis elegans to study this putative interaction. After observing behavioral modulation, mutant analysis and gene expression in C. elegans upon exposure to quercetin at a concentration that does not protect against MPTP, we constructed a homology-based dopamine transporter protein model to conduct a docking study. This led to suggestive evidence on how quercetin may act as a dopaminergic modulator by interacting with C. elegans' dopamine transporter and alter the nematode's exploratory behavior. Consistent with this model, quercetin controls C. elegans behavior in a way dependent on the presence of both the dopamine transporter (dat-1), which is up-regulated upon quercetin exposure, and the dopamine receptor 2 (dop-2), which appears to be mandatory for dat-1 up-regulation. Our data propose an interaction with the dopaminergic machinery that may help to establish the effects of quercetin as a neuromodulator.