Pharmacological inhibition of dopamine beta‐hydroxylase blocks cocaine‐induced reinstatement in rats

Abstract

Disulfiram (Antabuse) has recently shown promise as a pharmacotherapy for cocaine dependence, though the mechanisms underlying its efficacy are unclear. One of the many biochemical actions of disulfiram is inhibition of dopamine beta‐hydroxylase (DBH), the enzyme that converts dopamine to norepinephrine (NE); consequently, disulfiram reduces brain NE levels. Noradrenergic signaling is required for reinstatement of drug seeking in rats, a paradigm which is thought to model drug relapse. We therefore hypothesized that DBH inhibition underlies the therapeutic effects of disulfiram. To test this hypothesis, cocaine self‐administration studies were conducted in rats (N=5–8 per group) given pretreatments of vehicle, disulfiram (100 mg/kg i.p.) or the selective DBH inhibitor nepicastat (50 mg/kg i.p.). We found that neither disulfiram nor nepicastat altered lever pressing behavior during the maintenance phase of self‐administration. In contrast, both drugs blocked cocaine‐primed reinstatement of lever pressing following extinction. These results suggest that pharmacological DBH inhibition may be an effective treatment for cocaine dependence, potentially by preventing relapse.