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

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Gaval-Cruz, Meriem Schroeder, Jason P. Liles, L. Cameron Javors, Martin A. Weinshenker, David
Description	Country affiliation: United States Author Affiliation: Gaval-Cruz M ( Department of Human Genetics, Emory University, 301 Whitehead Biomedical Research Building, 615 Michael Street, Atlanta, GA 30322, USA.)
Abstract	The antialcoholism drug disulfiram has shown recent promise as a pharmacotherapy for treating cocaine dependence, probably via inhibition of dopamine beta-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.
File Format	HTM / HTML
ISSN	00913057
e-ISSN	18735177
DOI	10.1016/j.pbb.2008.02.009
Journal	Pharmacology Biochemistry and Behavior
Issue Number	4
Volume Number	89
Language	English
Publisher	Elsevier
Publisher Date	2008-06-01
Publisher Place	United States
Access Restriction	Open
Subject Keyword	Discipline Behavioral Sciences Discipline Biochemistry Discipline Pharmacology Alcohol Deterrents Toxicity Cocaine Disulfiram Dopamine Beta-hydroxylase Deficiency Seizures Chemically Induced Enzymology Administration & Dosage Animals Metabolism Antagonists & Inhibitors Genetics Drug Synergism Enzyme Inhibitors Pharmacology Imidazoles Mice Mice, Inbred C57bl Mice, Knockout Thiones Research Support, N.i.h., Extramural
Content Type	Text
Resource Type	Article
Subject	Biological Psychiatry Behavioral Neuroscience Biochemistry Clinical Biochemistry Toxicology Pharmacology

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