Modulation of dopamine D₁ receptors via histamine H₃ receptors is a novel therapeutic target for huntington’s disease

Early Huntington’s disease (HD) include over-activation of dopamine D1 receptors (D1 R), producing an imbalance in dopaminergic neurotransmission and cell death. To reduce D1 R over-activation, we present a strategy based on targeting complexes of D1 R and histamine H3 receptors (H3 R). Using an HD mouse striatal cell model and HD mouse organotypic brain slices we found that D1 R-induced cell death signaling and neuronal degeneration, are mitigated by an H3 R antagonist. We demonstrate that the D1 R-H3 R 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 H3 R antagonist prevented cognitive and motor learning deficits and the loss of heteromer expression. Taken together, our results indicate that D1R-H3 R heteromers play a pivotal role in dopamine signaling and represent novel targets for treating HD.