More recently, disulfiram was shown to be effective in treating cocaine addiction as well, even though alcohol and cocaine affect the nervous system in different ways.
Now, researchers at Emory University School of Medicine have identified how disulfiram may exert its effects, and have shown that a newer drug with fewer side effects works by the same mechanism.
The results are published online this week by the journal Neuropsychopharmacology. Research assistant professor Jason Schroeder, PhD, and graduate student Debra Cooper are co-first authors of the paper, and the research also involved collaborations with P. Michael Iuvone, PhD, director of research at the Emory Eye Center, Gaylen Edwards, DVM, PhD, head of the department of physiology and pharmacology at the University of Georgia's College of Veterinary Medicine, and Philip Holmes, PhD, professor of psychology at the University of Georgia.
"Disulfiram has several effects on the body: it interferes with alcohol metabolism, but it inhibits several other enzymes by sequestering copper, and can also damage the liver," says senior author David Weinshenker, PhD, associate professor of human genetics at Emory University School of Medicine. "We wanted to figure out how disulfiram was working so we could come up with safer and potentially more effective treatments."
In treating cocaine addiction, there are several challenges: not only getting people to stop taking the drug, but also preventing relapse. Cocaine boosts the levels of several neurotransmitters, including dopamine and norepinephrine, at the junctions between nerve cells by blocking the machinery the brain uses to remove them.
Under normal conditions, dopamine is important for the sensation of pleasure produced by natural rewards such as food or sex, Weinshenker says. Cocaine "hijacks" the dopamine system, which plays a large role in addiction. Similarly, norepinephrine has a role in attention and arousal, but its overactivation can trigger stress responses and relapse, he says.
Weinshenker's team showed that disulfiram prevents rats from seeking cocaine after a break, a model for addicts tempted to relapse. At the same time, it doesn't stop them from taking cocaine when first exposed to it, or from enjoying their food.
Disulfiram appears to work by inhibiting dopamine beta-hydroxylase, an enzyme required for the production of norepinephrine. A dose of disulfiram that lowers the levels of norepinephrine in the brain by about 40 percent is effective, while doses that do not reduce norepinephrine have no effect on relapse-like behavior in rats.
To confirm that the beneficial effects of disulfiram were because of dopamine beta-hydroxylase inhibition, the researchers turned to a drug called nepicastat, which was originally developed for the treatment of congestive heart failure in the 1990s.
"Nepicastat is a selective dopamine beta-hydroxylase inhibitor that does not sequester copper or impair a host of other enzymes like disulfiram," Weinshenker says. "We reasoned that if disulfiram is really working through dopamine beta-hydroxylase, then nepicastat might be a better alternative."
Researchers at the University of Texas Medical Branch at Galveston have recently completed a Phase I safety trial studying nepicastat for the treatment of cocaine addiction in human subjects.
Weinshenker is co-inventor on a patent on the use of dopamine beta-hydroxylase inhibitors for the treatment of cocaine dependence, and could benefit from their commercialization. This has been reviewed by Emory University's Conflict of Interest Committee, and a management plan is in place.
The research was supported by the National Institute of Drug Abuse and the National Eye Center.
Reference:J.P. Schroeder et al. Disulfiram Attenuates Drug-Primed Reinstatement of Cocaine Seeking via Inhibition of Dopamine â-Hydroxylase.
Neuropsychopharmacology, 35, page numbers TK (2010).
The Robert W. Woodruff Health Sciences Center of Emory University is an academic health science and service center focused on missions of teaching, research, health care and public service. Its components include the Emory University School of Medicine, Nell Hodgson Woodruff School of Nursing, and Rollins School of Public Health; Yerkes National Primate Research Center; Winship Cancer Institute of Emory University; and Emory Healthcare, the largest, most comprehensive health system in Georgia. Emory Healthcare includes: The Emory Clinic, Emory-Children's Center, Emory University Hospital, Emory University Hospital Midtown, Wesley Woods Center, and Emory University Orthopaedics & Spine Hospital. The Woodruff Health Sciences Center has a $2.5 billion budget, 17,600 employees, 2,500 full-time and 1,500 affiliated faculty, 4,700 students and trainees, and a $5.7 billion economic impact on metro Atlanta.
Learn more about Emory's health sciences: http://emoryhealthblog.com - @emoryhealthsci (Twitter) - http://emoryhealthsciences.org
Holly Korschun | EurekAlert!
Ambush in a petri dish
24.11.2017 | Friedrich-Schiller-Universität Jena
Meadows beat out shrubs when it comes to storing carbon
23.11.2017 | Norwegian University of Science and Technology
High-precision measurement of the g-factor eleven times more precise than before / Results indicate a strong similarity between protons and antiprotons
The magnetic moment of an individual proton is inconceivably small, but can still be quantified. The basis for undertaking this measurement was laid over ten...
Heat from the friction of rocks caused by tidal forces could be the “engine” for the hydrothermal activity on Saturn's moon Enceladus. This presupposes that...
The WHO reports an estimated 429,000 malaria deaths each year. The disease mostly affects tropical and subtropical regions and in particular the African continent. The Fraunhofer Institute for Silicate Research ISC teamed up with the Fraunhofer Institute for Molecular Biology and Applied Ecology IME and the Institute of Tropical Medicine at the University of Tübingen for a new test method to detect malaria parasites in blood. The idea of the research project “NanoFRET” is to develop a highly sensitive and reliable rapid diagnostic test so that patient treatment can begin as early as possible.
Malaria is caused by parasites transmitted by mosquito bite. The most dangerous form of malaria is malaria tropica. Left untreated, it is fatal in most cases....
The formation of stars in distant galaxies is still largely unexplored. For the first time, astron-omers at the University of Geneva have now been able to closely observe a star system six billion light-years away. In doing so, they are confirming earlier simulations made by the University of Zurich. One special effect is made possible by the multiple reflections of images that run through the cosmos like a snake.
Today, astronomers have a pretty accurate idea of how stars were formed in the recent cosmic past. But do these laws also apply to older galaxies? For around a...
Just because someone is smart and well-motivated doesn't mean he or she can learn the visual skills needed to excel at tasks like matching fingerprints, interpreting medical X-rays, keeping track of aircraft on radar displays or forensic face matching.
That is the implication of a new study which shows for the first time that there is a broad range of differences in people's visual ability and that these...
15.11.2017 | Event News
15.11.2017 | Event News
30.10.2017 | Event News
24.11.2017 | Physics and Astronomy
24.11.2017 | Health and Medicine
24.11.2017 | Earth Sciences