Abstract
The anti-alcoholism medication, disulfiram (Antabuse), decreases cocaine use in humans regardless of concurrent alcohol consumption and facilitates cocaine sensitization in rats, but the functional targets are unknown. Disulfiram inhibits dopamine β-hydroxylase (DBH), the enzyme that converts dopamine (DA) to norepinephrine (NE) in noradrenergic neurons. The goal of this study was to test the effects of chronic genetic or pharmacological DBH inhibition on behavioral responses to cocaine using DBH knockout (Dbh −/−) mice, disulfiram, and the selective DBH inhibitor, nepicastat. Locomotor activity was measured in control (Dbh +/−) and Dbh −/− mice during a 5 day regimen of saline+saline, disulfiram+saline, nepicastat+saline, saline+cocaine, disulfiram+cocaine, or nepicastat+cocaine. After a 10 day withdrawal period, all groups were administered cocaine, and locomotor activity and stereotypy were measured. Drug-naïve Dbh −/− mice were hypersensitive to cocaine-induced locomotion and resembled cocaine-sensitized Dbh +/− mice. Chronic disulfiram administration facilitated cocaine-induced locomotion in some mice and induced stereotypy in others during the development of sensitization, while cocaine-induced stereotypy was evident in all nepicastat-treated mice. Cocaine-induced stereotypy was profoundly increased in the disulfiram+cocaine, nepicastat+cocaine, and nepicastat+saline groups upon cocaine challenge after withdrawal in Dbh +/− mice. Disulfiram or nepicastat treatment had no effect on behavioral responses to cocaine in Dbh −/− mice. These results demonstrate that chronic DBH inhibition facilitates behavioral responses to cocaine, although different methods of inhibition (genetic vs. non-selective inhibitor vs. selective inhibitor) enhance qualitatively different cocaine-induced behaviors.
Highlights
The anti-alcoholism medication, disulfiram, has shown promise for reducing cocaine use in addicts in most, but not all studies, in a manner independent of alcohol intake, at higher doses and in non-alcoholic subjects [1,2,3,4,5,6,7,8,9,10,11,12,13]
The purpose of this study was to determine the effects of chronic Dopamine b-hydroxylase (DBH) inhibition on cocaine responses, and whether the disulfiraminduced facilitation of cocaine sensitization, reported previously in rats [18], was due to disulfiram’s ability to inhibit DBH
Many studies have speculated that disulfiram alters cocaine responses via DBH inhibition, they all lacked a DBH-deficient control group, a selective DBH inhibitor, chronic disulfiram administration, and/or assessment of brain NE levels, and were not designed to test the contribution of DBH
Summary
The anti-alcoholism medication, disulfiram, has shown promise for reducing cocaine use in addicts in most, but not all studies, in a manner independent of alcohol intake, at higher doses and in non-alcoholic subjects [1,2,3,4,5,6,7,8,9,10,11,12,13]. Identifying the functional targets of disulfiram, those that underlie its chronic effects on cocaine responses, could lead to safer and more effective alternatives for the treatment of cocaine dependence. Disulfiram increases self-reported ratings of psychostimulant aversion, such as anxiety, nervousness, paranoia, craving, and dysphoria in humans [1,7,19,20,21,22,23,24], and addicts with polymorphisms in the DBH gene that confer low DBH activity report higher levels of cocaine-induced paranoia [25,26]. Chronic disulfiram treatment or targeted disruption of the DBH gene each produce behavioral hypersensitivity to psychostimulants, including more pronounced cocaine aversion [18,30,31]
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