In sum, our study showing that H3R antagonists can prevent learning and memory deficits by blocking D1R in D1R-H3R complexes, along with the role of these heteromers on neuronal cell death, predict a critical role of the histaminergic system as modulator of the dopamine imbalance in HD, and may help to overcome the deleterious effects of directly manipulating DA-production and/or signaling, thus opening new and important alternatives for HD therapeutics. The gene discussed is HRH3; the disease is Huntington disease.