The general effects of cocaine are not well understood at the molecular level. What is known is that the dopamine D₁receptor plays an important role. Here we show that a key mechanism may be cocaine's blockade of the histamine H₃receptor-mediated inhibition of D₁receptor function. This blockade requires the σ₁receptor and occurs upon cocaine binding to σ₁-D₁-H₃receptor complexes. The cocaine-mediated disruption leaves an uninhibited D₁receptor that activates G_s, freely recruits β-arrestin, increases p-ERK 1/2 levels, and induces cell death when over activated. Usingin vitroassays with transfected cells and inex vivoexperiments using both rats acutely treated or self-administered with cocaine along with mice depleted of σ₁receptor, we show that blockade of σ₁receptor by an antagonist restores the protective H₃receptor-mediated brake on D₁receptor signaling and prevents the cell death from elevated D₁receptor signaling. These findings suggest that a combination therapy of σ₁R antagonists with H₃receptor agonists could serve to reduce some effects of cocaine.