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.