In a paper published in the November 3, 2010 issue of Neuropsychopharmacology, the researchers showed that alcohol consumption in rodents was significantly decreased by two compounds that target neuronal nicotinic acetylcholine receptor (nAChR) subtype α3ß4*.
nAChRs are proteins found in the brain and broader central nervous system that mediate the effects of substances such as nicotine. Recent human genetic studies have shown that the genes encoding the α3ß4* subtype are of significant importance for susceptibility to both alcohol and nicotine dependence.
“The problem has been translating these important genetic findings into more effective medications for people,” said co-senior author Selena E. Bartlett, PhD, director of the Preclinical Development group at the Gallo Center. The lead author of the study is Susmita Chatterjee, PhD, of the Gallo Center.
The work was done in collaboration with scientists led by co-senior author Hans Rollema, PhD, in the Neuroscience Research Unit at Pfizer Inc.
One of the new compounds, CP-601932, has been shown in a clinical study to be safe in humans, notes Bartlett. She recommends a clinical study to evaluate the compound’s efficacy and potential benefits in treating both alcohol and nicotine dependence.
The other compound is PF-4575180. Both were developed by Pfizer.
“Alcohol and nicotine addiction are often treated as separate disorders,” Bartlett says, “despite the fact that 60 to 80 percent of heavy drinkers smoke tobacco. There are very few effective strategies for treating these disorders separately, let alone together. Our data suggest that by targeting specific nAChR subtypes, it may be possible to treat both alcohol and nicotine dependence with one medication.”
Significantly, while the compounds had a significant effect on the rodents’ alcohol consumption, their intake of sucrose was not affected. “This indicates that unlike currently approved alcohol abuse medications, the compounds do not interfere with the brain’s natural reward system in a larger way,” says Bartlett.
Co-authors of the study are Pia Steensland, PhD, of the Karolinska Institutet, Sweden, Jeffrey A. Simms, BSc, and Joan Holgate, BSc, of the Gallo Center, and Jotham W. Coe, PhD, Raymond S. Hurst, PhD, Christopher L. Shaffer, PhD, and John Lowe, PhD, of Pfizer.
The study was supported by funds from the National Institutes of Health, the US Department of Defense, the State of California, the Foundation BLANCEFLOR Boncompagni-Ludovisi, née Bildt, the Sweden-America Foundation, and Insamlingsstiftelsen Hjärnfonden/The Swedish Brain Foundation.
The UCSF-affiliated Ernest Gallo Clinic and Research Center is one of the world’s preeminent academic centers for the study of the biological basis of alcohol and substance use disorders. Gallo Center discoveries of potential molecular targets for the development of therapeutic medications are extended through preclinical and proof-of-concept clinical studies.
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