Alzheimer's disease (AD) is a neurodegenerative disorder causing progressive memory loss and cognitive dysfunction. Anti-AD strategies targeting cell receptors consider them as isolated units. However, many cell surface receptors cooperate and physically contact each other forming complexes having different biochemical properties than individual receptors. We here report the discovery of dopamine D₁, histamine H₃, and N-methyl-D-aspartate (NMDA) glutamate receptor heteromers in heterologous systems and in rodent brain cortex. Heteromers were detected by co-immunoprecipitation and in situ proximity ligation assays (PLA) in the rat cortex where H₃ receptor agonists, via negative cross-talk, and H₃ receptor antagonists, via cross-antagonism, decreased D₁ receptor agonist signaling determined by ERK1/2 or Akt phosphorylation, and counteracted D₁ receptor-mediated excitotoxic cell death. Both D₁ and H₃ receptor antagonists also counteracted NMDA toxicity suggesting a complex interaction between NMDA receptors and D₁-H₃ receptor heteromer function. Likely due to heteromerization, H₃ receptors act as allosteric regulator for D₁ and NMDA receptors. By bioluminescence resonance energy transfer (BRET), we demonstrated that D₁ or H₃ receptors form heteromers with NR1A/NR2B NMDA receptor subunits. D₁-H₃-NMDA receptor complexes were confirmed by BRET combined with fluorescence complementation. The endogenous expression of complexes in mouse cortex was determined by PLA and similar expression was observed in wild-type and APP/PS1 mice. Consistent with allosteric receptor-receptor interactions within the complex, H₃ receptor antagonists reduced NMDA or D₁ receptor-mediated excitotoxic cell death in cortical organotypic cultures. Moreover, H₃ receptor antagonists reverted the toxicity induced by ß_1-42-amyloid peptide. Thus, histamine H₃ receptors in D₁-H₃-NMDA heteroreceptor complexes arise as promising targets to prevent neurodegeneration.