WASHINGTON, DC March 6, 2007 -- A study of alcohol-dependent animals shows that a newly discovered compound that blocks chemical signals active during the brain's response to stress effectively stops excessive drinking and prevents relapse.
The new, synthetic compound, known as MTIP, also muted the anxiety that typically develops in rats experiencing the equivalent of a hangover. Such stress is linked with higher levels of a brain chemical called corticotropin-releasing factor (CRF), which is also thought to trigger relapse in rats that have developed a long-term dependency on alcohol. The research, by Markus Heilig, MD, PhD, at the National Institute on Alcohol Abuse and Alcoholism (NIAAA), and his team, appears in the March 7 issue of The Journal of Neuroscience.
"This study shows the activity of a compound that potentially could be used in human subjects," says George Koob, PhD, of the Scripps Research Institute. "It moves the field over another translational barrier, closer to the day when the dark side of addiction is treated."
The new findings build on previous work showing the effectiveness of blocking certain CRF receptors--proteins that bind CRF and make it active--in treating alcohol dependence in animals. CRF levels in the brain rise in the short term after drinking; in subjects that are not dependent, this activation returns to normal within a day or so. The new study shows that the CRF system becomes overactive in the long term in animals with a history of alcohol dependence, increasing the risk for relapse.
Heilig and his team showed that MTIP blocked the activity of CRF in stressful situations without affecting its activity under ordinary circumstances. They studied rats that had been put through several cycles of heavy alcohol consumption and withdrawal to create dependency, as well as animals selectively bred to consume more alcohol. Injections of MTIP prevented excessive drinking of alcohol in both cases and eliminated the rats' susceptibility to relapse under stress. Yet the compound did not affect their native curiosity or lower levels of drinking alcohol in rats that were not alcohol-dependent.
In addition to alcoholism, the compound may prove to be useful in the treatment of depression or anxiety disorders, in which CRF levels can be especially high.
The compound or similar molecules can be given orally, reach the brain in sufficient amounts to block more than 90 percent of certain brain CRF receptors, and do not accumulate in other organs, most importantly the liver, in ways that would cause concerns about potential side effects, says Heilig.
The work was a collaborative project between NIAAA and Eli Lilly and Co.
The Journal of Neuroscience is published by the Society for Neuroscience, an organization of more than 36,500 basic scientists and clinicians who study the brain and nervous system. Heilig can be reached at Markus.Heilig@mail.nih.gov.