Cocaine Disrupts Histamine H₃ Receptor Modulation of Dopamine D₁ Receptor Signaling: σ₁-D₁-H₃ Receptor Complexes as Key Targets for Reducing Cocaine's Effects

Abstract

The general effects of cocaine are not well understood at the molecular level. What is known is that the dopamine D₁ receptor plays an important role. Here we show that a key mechanism may be cocaine's blockade of the histamine H₃ receptor-mediated inhibition of D₁ receptor function. This blockade requires the σ₁ receptor and occurs upon cocaine binding to σ₁-D₁-H₃ receptor complexes. The cocaine-mediated disruption leaves an uninhibited D₁ receptor that activates G_s, freely recruits β-arrestin, increases p-ERK 1/2 levels, and induces cell death when over activated. Using in vitro assays with transfected cells and in ex vivo experiments using both rats acutely treated or self-administered with cocaine along with mice depleted of σ₁ receptor, we show that blockade of σ₁ receptor by an antagonist restores the protective H₃ receptor-mediated brake on D₁ receptor signaling and prevents the cell death from elevated D₁ receptor signaling. These findings suggest that a combination therapy of σ₁R antagonists with H₃ receptor agonists could serve to reduce some effects of cocaine.