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Researchers at the University of California, San Francisco (UCSF), have devised a two-drug therapeutic approach for alcohol use disorder (AUD), which studies in mice suggest doesn’t have the side effects or complications associated with current treatment regimens, and which could feasibly be applicable to other drugs that are sometimes abused. The team showed that using both the drugs—one of which is already in clinical oncology trials— effectively made it possible block the AUD target mTORC1 specifically in the brain, and not in the periphery. When tested in mice, treatment with both drugs attenuated alcohol seeking and drinking.
Reporting on their studies in Nature Communications, the team concluded, “ … the approach described herein, enabling the separation between the desirable, CNS [central nervous system]-mediated actions of a drug versus the undesirable periphery-mediated drug effects could in principle be used for the development of other CNS-targeted therapeutic approaches.” Senior author Dorit Ron, PhD, a professor of neurology, and colleagues, describe their findings in a paper titled, “Brain-specific inhibition of mTORC1 eliminates side effects resulting from mTORC1 blockade in the periphery and reduces alcohol intake in mice.”
Alcohol use disorder (AUD) is estimated to affect 10–15% of the population, causing significant medical, social, and economic burdens, the authors wrote. And while the incidence of AUD diagnosis has increased by 35% in the United States between 2001 and 2013, drug treatments for the condition are limited. “ … only three drugs, naltrexone, acamprosate, and disulfiram, have been approved by the U.S. Food and Drug Administration (FDA) as therapeutics for AUD,” the team noted. “Thus, there is a need to develop additional effective medications to alleviate phenotypes such as binge drinking, craving, and relapse.”
The basis of the newly reported study is the idea that AUD and other substance abuse disorders are the result of reinforced pathways in the brain, and that those pathways can be blocked or redirected, ending cravings and habitual behavior. “Alcohol use disorder is really a process of maladapted learning and memory,” said Ron. “Alcohol is rewarding, and we learn to associate alcohol, and even the environment in which we drink the alcohol, with that reward.”
Current pharmaceutical options for AUD attempt to change behavior by making alcohol consumption an unpleasant experience, and some require patients to abstain for several days before beginning treatment. Since 2010, Ron, who is also faculty in the Weill Institute for Neurosciences, has taken a different approach, studying the role of the enzyme mTORC1 in the creation of those memories and associations, with the goal of creating an effective drug that can treat the neurological causes of AUD.
Ordinarily, mTORC1 is involved in brain plasticity, helping to create connections between neurons that reinforce memory. “mTORC1 has an important role in synaptic plasticity, and learning, and memory,” the team continued. “mTORC1 malfunction in the CNS has been linked to aging process, neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease, neurodevelopmental disorders such as autism, as well as psychiatric disorders including addiction.”
In previous work, Ron showed that consuming alcohol activates the enzyme in the brain. “Studies in rodents suggest that mTORC1 plays a crucial role in mechanisms underlying phenotypes such as heavy alcohol intake, habit, and relapse. Thus, mTORC1 inhibitors, which are used in the clinic, are promising therapeutic agents to treat AUD,” the investigators commented.
Ron has also shown that blocking the activity of mTORC1 with the FDA-approved compound rapamycin—which is used to treat some types of cancer and suppress immune response in transplant patients—can halt cravings in a mouse model of alcohol use disorder. But mTORC1 plays roles in metabolism and liver function, and people taking it for an extended period often develop liver toxicity, glucose intolerance, and other side effects.
For some of her previous work, Ron had teamed up with Kevan Shokat, PhD, a professor of Cellular Molecular Pharmacology, who had created RapaLink-1, a molecule similar to rapamycin, which he designed specifically to keep a tight grip on mTORC1 and completely subdue it. A version of the drug is now being tested in oncology clinical trials.
Shokat’s thought was that, since Ron is concerned only with the activity of mTORC1 in the brain, that’s the only place where RapaLink-1 or rapamycin needs to be effective. So Ziyang Zhang, PhD, a postdoctoral researcher in Shokat’s lab, designed a second molecule that would latch onto RapaLink-1 or rapamycin, and essentially negate its effects, but that was too big to cross the blood-brain barrier.
In other words, Shokat reasoned that RapaLink-1 or rapamycin could be administered and allowed to circulate throughout the body. Once it had a chance to reach the brain, Rapablock could be given, halting the activity of Rapalink-1 everywhere except in that targeted area. “We hypothesized that when RapaBlock will be co-administered with RapaLink-1, mTORC1 activity will be protected in the periphery while inhibited in the brain,” the team explained. “We further predicted that this approach would block the undesirable side effects observed after chronic inhibition of the kinase.”
And when Yann Ehinger, PhD, a postdoctoral researcher in Ron’s lab, tested the two-drug approach in a mouse model of AUD, it was found to work like a charm. “We could see these side effects in mice who are taking rapamycin or RapaLink-1, and then when you give Rapablock, it’s like magic, the side effects are gone,” said Ron.
“We show herein that RapaBlock provides full protection of mTORC1 activity in the periphery,” the investigators reported in their paper. “The small molecule also prevents the detrimental side effects, resulting from chronic inhibition of the kinase in the periphery. We further present preclinical proof of concept data for the potential utility of the RapaLink-1+RapaBlock dual-drug administration strategy for the treatment of AUD.”
They say that the results of their studies, combined with data from prior studies, suggests that the Rapalink-1+RapaBlock dual-drug strategy “… may potentially be used in humans.” Shokat said a similar strategy is being explored for treating other conditions, such as Parkinson’s disease. Those trials involve different drugs, but the underlying principle is the same: one drug results in the desired effect in the brain, while its activity is blocked by a molecule that isn’t able to cross the blood-brain barrier. “Furthermore, the approach described herein, enabling the separation between the desirable, CNS-mediated actions of a drug versus the undesirable periphery-mediated drug effects could in principle be used for the development of other CNS-targeted therapeutic approaches.”
And with prior rodent studies indicating that rapamycin therapy can inhibit the consolidation and reconsolidation of fear memory, the team says the new strategy may also have potential use for treating post-traumatic stress disorder.
Ron believes that tackling addiction from this neurological perspective has potential for broad applications. She notes that while we see addiction with a wide chemical array of molecules—alcohol, nicotine, cocaine, opiates, and the like—the addictive behavior that results from each is the same.
“It’s really quite striking,” she said, adding that a whole body of study points to the possibility of mTORC1 being a kind of supermolecule that is activated by all misused drugs. “If that’s true,” Ron said, “It suggests that this approach can be applied to other drugs of abuse as well, essentially solving the problem of addiction.”
