Disulfiram Attenuates Drug-Primed Reinstatement of Cocaine Seeking via Inhibition of Dopamine β-Hydroxylase

Abstract

The anti-alcoholism medication disulfiram (Antabuse) inhibits aldehyde dehydrogenase (ALDH), which results in the accumulation of acetaldehyde upon ethanol ingestion and produces the aversive “Antabuse reaction” that deters alcohol consumption. Disulfiram has also been shown to deter cocaine use, even in the absence of an interaction with alcohol, indicating the existence of an ALDH-independent therapeutic mechanism. We hypothesized that disulfiram’s inhibition of dopamine β-hydroxylase (DBH), the catecholamine biosynthetic enzyme that converts dopamine (DA) to norepinephrine (NE) in noradrenergic neurons, underlies the drug’s ability to treat cocaine dependence. We tested the effects of disulfiram on cocaine and food self-administration behavior and drug-primed reinstatement of cocaine seeking in rats. We then compared the effects of disulfiram with those of the selective DBH inhibitor, nepicastat. Disulfiram, at a dose (100 mg/kg, i.p.) that reduced brain NE by ~40%, did not alter responding for food or cocaine on a fixed ratio 1 (FR1) schedule, whereas it completely blocked cocaine-primed (10 mg/kg, i.p.) reinstatement of drug seeking following extinction. A lower dose of disulfiram (10 mg/kg) that did not reduce NE had no effect on cocaine-primed reinstatement. Nepicastat recapitulated the behavioral effects of disulfiram (100 mg/kg) at a dose (50 mg/kg, i.p.) that produced a similar reduction in brain NE. Food-primed reinstatement of food seeking was not impaired by DBH inhibition. Our results suggest that disulfiram’s efficacy in the treatment of cocaine addiction is associated with the inhibition of DBH and interference with the ability of environmental stimuli to trigger relapse.

BAP updated guidelines: evidence-based guidelines for the pharmacological management of substance abuse, harmful use, addiction and comorbidity: recommendations from BAP

“…This deters people from drinking (Fuller and Roth, 1979) (Ib). Disulfiram also blocks dopamine-b-hydroxylase in the brain, so increasing dopamine and reducing noradrenaline, and this may contribute to its clinical effects in alcoholism or cocaine addiction (see later; Schroeder et al, 2010).…”

Aldehyde Dehydrogenase Inhibitors: a Comprehensive Review of the Pharmacology, Mechanism of Action, Substrate Specificity, and Clinical Application

“…This is thought to involve disulfiram inhibition of dopamine ␤-hydroxylase (Barth and Malcolm, 2010;Schroeder et al, 2010), the copper-dependent enzyme required for metabolism of dopamine to norepinephrine in noradrenergic neurons. The resultant disulfiram-induced decrease in norepinephrine release from noradrenergic nerves impinging on midbrain dopaminergic neurons is thought to reduce excitation of these dopaminergic neurons and thereby attenuate the cocaine-induced euphoria (Gaval-Cruz and Weinshenker, 2009).…”

Dopamine β-Hydroxylase Inhibitors Enhance the Discriminative Stimulus Effects of Cocaine in Rats

“…For example, whereas administration of disulfiram or nepicastat enhances the discriminative stimulus effects of cocaine (present results), cocaine-induced locomotor sensitization (Haite et al, 2003;Gaval-Cruz et al, 2012), and cocaine-induced seizures (Gaval-Cruz et al, 2008), their administration reduces progressive ratio responding for cocaine and the reinstatement of previously extinguished cocaine-seeking behavior induced by a cocaine prime, cocaine-associated cues, or stress (Schroeder et al, 2010(Schroeder et al, , 2013. How can we reconcile both enhancements and suppressions of cocaine-induced behaviors with the ability of DBH inhibitors to reduce cocaine use in clinical populations?…”

“…Because cocaine-induced increases in DA within the NAc rather than the PFC predominantly mediate the discriminative stimulus effects of cocaine (Callahan et al, 1997), it is not surprising that in the present studies, cocaine failed to generalize to either disulfiram or nepicastat. Importantly, our dose range (up to 100 mg/kg disulfiram and 56 mg/kg nepicastat) and pretreatment time (2 hours) were chosen based on our own previous work and the aforementioned microdialysis studies, which reported maximal increases in DA levels within the PFC and reductions of NE levels across multiple brain regions using these parameters (Schroeder et al, 2010;Devoto et al, 2012Devoto et al, , 2013. Thus, the experiments were optimized to detect the presence of a cocaine-like interoceptive stimulus.…”

“…The percentage of cocaine-appropriate responding, as well as response rate, was averaged across all four components for individual animals and then a group average was determined. The pretreatment time and dose ranges for disulfiram and nepicastat were chosen based on previous studies indicating effective reductions of NE content using these parameters (Schroeder et al, 2010). For combination studies, disulfiram (0-100 mg/kg i.p.)…”