Abnormalities of Dopamine D(3) Receptor Signaling in the Diseased Brain

Dopamine D(3) receptors (D(3)R) modulate neuronal activity in several brain regions including cortex, striatum, cerebellum, and hippocampus. A growing body of evidence suggests that aberrant D(3)R signaling contributes to multiple brain diseases, such as Parkinson’s disease, essential tremor, schizophrenia, and addiction. In line with these findings, D(3)R has emerged as a potential target in the treatment of neurological disorders. However, the mechanisms underlying neuronal D(3)R signaling are poorly understood, either in healthy or diseased brain. Here, I review the molecular mechanisms involved in D(3)R signaling via monomeric D(3)R and heteromeric receptor complexes (e.g., D(3)R-D(1)R, D(3)R-D(2)R, D(3)R-A(2a)R, and D(3)R-D(3)nf). I focus on D(3)R 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 D(3)R that has been associated with brain dysfunction. I conclude with a description of basic mechanisms that modulate D(3)R signaling such as desensitization, as disruption of these mechanisms may underlie pathological changes in D(3)R signaling. Because several lines of evidence support the idea that imbalances in D(3)R signaling alter neural function, a better understanding of downstream D(3)R pathways is likely to reveal novel therapeutic strategies toward dopamine-related brain disorders.