Disulfiram attenuates drug-primed reinstatement of cocaine seeking via inhibition of dopamine β-hydroxylase.
The antialcoholism 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 the response for food or cocaine on a fixed ratio 1 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.
Schroeder
Jason P
JP
Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA.
Cooper
Debra A
DA
Schank
Jesse R
JR
Lyle
Megan A
MA
Gaval-Cruz
Meriem
M
Ogbonmwan
Yvonne E
YE
Pozdeyev
Nikita
N
Freeman
Kimberly G
KG
Iuvone
P Michael
PM
Edwards
Gaylen L
GL
Holmes
Philip V
PV
Weinshenker
David
D
D000427:Alcohol Deterrents / Q000494:pharmacology*; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D003042:Cocaine / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D003216:Conditioning, Operant / Q000187:drug effects*; D004221:Disulfiram / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism; D004299:Dopamine beta-Hydroxylase / Q000037:antagonists & inhibitors*; D004347:Drug Interactions; D005108:Extinction, Psychological / Q000187:drug effects*; D005502:Food; D007093:Imidazoles / Q000494:pharmacology; D008297:Male; D009638:Norepinephrine / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012646:Self Administration; D013871:Thiones / Q000494:pharmacology
D000427:Alcohol Deterrents; D007093:Imidazoles; D013871:Thiones; D004299:Dopamine beta-Hydroxylase; D003042:Cocaine; D004221:Disulfiram; C109487:nepicastat; D004298:Dopamine; D009638:Norepinephrine