Chronic Inhibition of Dopamine beta-Hydroxylase Facilitates Behavioral Responses to Cocaine in Mice

• Authors: Meriem Gaval-Cruz, Emory University; Larry Cameron Liles, Emory University; Paul Iuvone, Emory University; David Weinshenker, Emory University
• Journal Title: PLoS ONE
• Volume: Volume 7, Number 11
• Publisher: Public Library of Science | 2012-11-27, Pages e50583-e50583
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.1371/journal.pone.0050583
• Subjects: Health Sciences, Opthamology; Biology, Genetics
• Keywords: Science & Technology; Multidisciplinary Sciences; Science & Technology - Other Topics; MULTIDISCIPLINARY SCIENCES; PLACEBO-CONTROLLED TRIAL; INDUCED REINSTATEMENT; DISULFIRAM TREATMENT; LOCOMOTOR-ACTIVITY; ALCOHOL DEPENDENCE; PREFRONTAL CORTEX; DRUG-METABOLISM; NOREPINEPHRINE; ADDICTION; SEEKING

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.