Selena Bartlett
Rats that drink like humans afflicted with alcoholism cut their drinking dramatically when treated with a new drug prototype — even after treatment ends.
According to a new report by researchers at the UCSF-affiliated Ernest Gallo Clinic and Research Center, rats treated with an experimental compound dubbed SoRI-9409 drank less than similarly addicted rats treated with naltrexone, the best drug now on the market to treat alcoholism.
This success in curbing drinking in rats is based on new thinking about which pathways and molecules in the brain ought to be targeted to treat alcohol addiction.
The research is based on a technique for inducing alcohol addiction that more accurately reproduces aspects of habituation seen in human alcohol addicts, as distinct from binge drinkers or social drinkers, the researchers say. If the scientists had not used this novel approach, they might not have observed the same encouraging results with the experimental treatment.
SoRI-9409 is made by the Southern Research Institute, a not-for-profit drug discovery and development organization based in Birmingham, Alabama.
Naltrexone appears to benefit some patients by blocking the brain’s opioid receptors. These same receptor molecules are best known for attaching to the addictive drug morphine or to the body’s own endorphins, which are produced to provide pain relief. But while naltrexone mainly blocks signals transmitted through a type of opioid receptor called mu, the new compound mainly blocks a different opioid receptor called delta.
This difference is likely to account for the greater effectiveness of the new drug prototype, the researchers say, and may lead to new strategies for developing drugs to fight alcoholism.
“We would like to move forward with drug development in collaboration with the Southern Research Institute, and get a drug into clinical trials,” says study leader Selena Bartlett, PhD, director of the Preclinical Development Group at the Ernest Gallo Clinic and Research Center at UCSF.
The new findings were published online in Biological Psychiatry on September 11 and will appear in the December print edition of the journal. Subramaniam Ananthan of the Southern Research Institute discovered the drug, and Bartlett’s research team has shown how the molecule achieves its effects in the brain.
In the most striking experiment, the researchers habituated 12 “alcohol-naïve” rats by giving them access every other day to a water bottle containing 20 percent ethanol. In addition, the rats also had unlimited access to pure water. In comparison with popular methods that rely on using sugar to coax rats to drink, it takes less time for rats to develop a preference for alcohol with Bartlett’s approach.
The sugar-aided alcohol habituation method results in rats that are more like social drinkers, she says. In contrast, with the sugar-free regimen, Bartlett says, “even though they always have access to pure water, we can induce rats to drink quite a lot of alcohol.”
Once rats exhibited prodigious alcohol consumption that remained stable for six weeks, the researchers gave them four weeks of daily treatment with naltrexone or SoRI-9409, or a third experimental drug, naltrindole.
In these heavily drinking rats, the reduction in alcohol consumption achieved with SoRI-9409 was three times greater than the reduction obtained with naltrexone treatment. Even up to four weeks after treatment ended, rats treated with SoRI-9409 still consumed less alcohol than they had before treatment, while rats treated with naltrexone resumed drinking as before when treatment ended.
The rats in the study did not exhibit obvious behavioral abnormalities due to treatment with SoRI-9409. “Our compound does not cause anxiety; it’s not rewarding, as an addictive drug would be; and it does not interfere with morphine-induced analgesia, as naltrexone does,” says Bartlett.
The research was funded by a grant from the state of California for medical research on alcoholism and substance abuse and a grant from the US Department of Defense.
Last year, Bartlett led another study in which researchers found that a Pfizer drug already marketed for the treatment of nicotine addiction also is effective in reducing drinking in rats. A clinical study of the Pfizer drug, called verenicline, is expected to begin within months, Bartlett says.
“Alcoholism is a complex disease,” Bartlett says. “We think it’s going to take multiple, different types of treatment to benefit different people.”
