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

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 Gs, 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.