Modulation of dopamine D ₁ receptors via histamine H ₃ receptors is a novel therapeutic target for Huntington's disease

Early Huntington's disease (HD) include over-activation of dopamine D₁ receptors (D₁R), producing an imbalance in dopaminergic neurotransmission and cell death. To reduce D₁R over-activation, we present a strategy based on targeting complexes of D₁R and histamine H₃ receptors (H₃R). Using an HD mouse striatal cell model and HD mouse organotypic brain slices we found that D₁R-induced cell death signaling and neuronal degeneration, are mitigated by an H₃R antagonist. We demonstrate that the D₁R-H₃R heteromer is expressed in HD mice at early but not late stages of HD, correlating with HD progression. In accordance, we found this target expressed in human control subjects and low-grade HD patients. Finally, treatment of HD mice with an H₃R antagonist prevented cognitive and motor learning deficits and the loss of heteromer expression. Taken together, our results indicate that D₁R - H₃R heteromers play a pivotal role in dopamine signaling and represent novel targets for treating HD.

Keywords: dopamine; g-protein coupled receptors; histamine; huntington's disease; mouse; neuroscience.