In the present study, we demonstrate that 1) excess dopamine signaling via D1R leads to cell death by activating the p38 pathway; 2) D1R-H3R complexes are found within the striatum, cortex and hippocampus of WT mice and in HD mice at early but not late disease stages; 3) targeting D1R via D1R-H3R complexes can slow progression of the disease in early but not late stages when the complexes are lost; and 4) D1R-H3R complexes are expressed in the human brain and thus represent potential therapeutic targets. Here, DRD1 is linked to Huntington disease.