Effects of disulfiram and dopamine beta-hydroxylase knockout on cocaine-induced seizures.
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.
Gaval-Cruz
Meriem
M
Department of Human Genetics, Emory University, 301 Whitehead Biomedical Research Building, 615 Michael Street, Atlanta, GA 30322, USA.
Schroeder
Jason P
JP
Liles
L Cameron
LC
Javors
Martin A
MA
Weinshenker
David
D
D000427:Alcohol Deterrents / Q000008:administration & dosage / Q000633:toxicity*; D000818:Animals; D003042:Cocaine / Q000008:administration & dosage / Q000378:metabolism / Q000633:toxicity*; D004221:Disulfiram / Q000008:administration & dosage / Q000633:toxicity*; D004299:Dopamine beta-Hydroxylase / Q000037:antagonists & inhibitors / Q000172:deficiency* / Q000235:genetics; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D007093:Imidazoles / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012640:Seizures / Q000139:chemically induced* / Q000201:enzymology*; D013871:Thiones / Q000494:pharmacology
D000427:Alcohol Deterrents; D004791:Enzyme Inhibitors; D007093:Imidazoles; D013871:Thiones; D004299:Dopamine beta-Hydroxylase; D003042:Cocaine; D004221:Disulfiram; C109487:nepicastat