Effects of disulfiram and dopamine beta-hydroxylase knockout on cocaine-induced seizures

Meriem Gaval-Cruz, Jason P. Schroeder, L. Cameron Liles, Martin A. Javors, David Weinshenker

Research output: Contribution to journalArticle

16 Scopus citations

Abstract

The antialcoholism drug disulfiram has shown recent promise as a pharmacotherapy for treating cocaine dependence, probably via inhibition of dopamine β-hydroxylase (DBH), the enzyme that catalyzes the conversion of dopamine (DA) to norepinephrine (NE). We previously showed that DBH knockout (Dbh -/-) mice, which lack NE, are susceptible to seizures and are hypersensitive to the psychomotor, rewarding, and aversive effects of cocaine, suggesting that disulfiram might exacerbate cocaine-induced seizures (CIS) by inhibiting DBH. To test this, we examined CIS in wild-type and Dbh -/- mice following administration of disulfiram or the selective DBH inhibitor nepicastat. We found that Dbh genotype had no effect on CIS probability or frequency, whereas disulfiram, but not nepicastat, increased the probability of having CIS in both wild-type and Dbh -/- mice. Both disulfiram and nepicastat increased CIS frequency in wild-type but not Dbh -/- mice. There were no genotype or treatment effects on serum cocaine levels, except for an increase in disulfiram-treated Dbh -/- mice at the highest dose of cocaine. These results suggest that disulfiram enhances CIS via two distinct mechanisms: it both increases CIS frequency by inhibiting DBH and increases CIS frequency in a DBH-independent manner.

Original languageEnglish (US)
Pages (from-to)556-562
Number of pages7
JournalPharmacology Biochemistry and Behavior
Volume89
Issue number4
DOIs
StatePublished - Jun 1 2008

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Keywords

  • Cocaine
  • Disulfiram
  • Dopamine beta-hydroxylase
  • Nepicastat
  • Norepinephrine
  • Seizure

ASJC Scopus subject areas

  • Biochemistry
  • Toxicology
  • Pharmacology
  • Clinical Biochemistry
  • Biological Psychiatry
  • Behavioral Neuroscience

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