Abnormalities of Dopamine D₃ Receptor Signaling in the Diseased Brain

Dopamine D₃ receptors (D₃R) modulate neuronal activity in several brain regions including cortex, striatum, cerebellum, and hippocampus. A growing body of evidence suggests that aberrant D₃R signaling contributes to multiple brain diseases, such as Parkinson's disease, essential tremor, schizophrenia, and addiction. In line with these findings, D₃R has emerged as a potential target in the treatment of neurological disorders. However, the mechanisms underlying neuronal D₃R signaling are poorly understood, either in healthy or diseased brain. Here, I review the molecular mechanisms involved in D₃R signaling via monomeric D₃R and heteromeric receptor complexes (e.g., D₃R-D₁R, D₃R-D₂R, D₃R-A_2aR, and D₃R-D₃nf). I focus on D₃R signaling pathways that, according to recent reports, contribute to pathological brain states. In particular, I describe evidence on both quantitative (e.g., increased number or affinity) and qualitative (e.g., switched signaling) changes in D₃R that has been associated with brain dysfunction. I conclude with a description of basic mechanisms that modulate D₃R signaling such as desensitization, as disruption of these mechanisms may underlie pathological changes in D₃R signaling. Because several lines of evidence support the idea that imbalances in D₃R signaling alter neural function, a better understanding of downstream D₃R pathways is likely to reveal novel therapeutic strategies toward dopamine-related brain disorders.