Addiction Relapse Might Be Thwarted By Turning Off Brain Trigger

Researchers at the Ernest Gallo Clinic and Research Center at UC San Francisco have been able to identify and deactivate a brain pathway linked to memories that cause alcohol cravings in rats, a finding that may one day lead to a treatment option for people who suffer from alcohol abuse disorders and other addictions.

In the study, researchers were able to prevent the addicted animals from seeking alcohol and drinking it, the equivalent of relapse.

“One of the main causes of relapse is craving, triggered by the memory by certain cues – like going into a bar, or the smell or taste of alcohol,” said lead author Segev Barak, PhD, at the time a postdoctoral fellow in the lab of co-senior author Dorit Ron, PhD, a Gallo Center investigator and UCSF professor of neurology.

“We learned that when rats were exposed to the smell or taste of alcohol, there was a small window of opportunity to target the area of the brain that reconsolidates the memory of the craving for alcohol and to weaken or even erase the memory, and thus the craving” he said.

The study, also supervised by co-senior author Patricia H. Janak, PhD, a Gallo Center investigator and UCSF professor of neurology, was published online on June 23 in Nature Neuroscience.

Neural Mechanism That Triggers Alcohol Memory

In the first phase of the study, rats had the choice to freely drink water or alcohol over the course of seven weeks, and during this time developed a high preference for alcohol.

In the next phase, they had the opportunity to access alcohol for one hour a day, which they learned to do by pressing a lever. They were then put through a 10-day period of abstinence from alcohol.

Following this period, the animals were exposed for five minutes to just the smell and taste of alcohol, which cued them to remember how much they liked drinking it. The researchers then scanned the animals’ brains, and identified the neural mechanism responsible for the reactivation of the memory of the alcohol – a molecular pathway mediated by an enzyme known as mammalian target of rapamycin complex 1 (mTORC1).

They found that just a small drop of alcohol presented to the rats turned on the mTORC1 pathway specifically in a select region of the amygdala, a structure linked to emotional reactions and withdrawal from alcohol, and cortical regions involved in memory processing.

They further showed that once mTORC1 was activated, the alcohol-memory stabilized (reconsolidated) and the rats relapsed on the following days, meaning in this case, that they started again to push the lever to dispense more alcohol.

“The smell and taste of alcohol were such strong cues that we could target the memory specifically without impacting other memories, such as a craving for sugar,” said Barak, who added that the Ron research group has been doing brain studies for many years and has never seen such a robust and specific activation in the brain.

Drug that Erases the Memory of Alcohol

In the next part of the study, the researchers set out to see if they could prevent the reconsolidation of the memory of alcohol by inhibiting mTORC1, thus preventing relapse. When mTORC1 was inactivated using a drug called rapamycin, administered immediately after the exposure to the cue (smell, taste), there was no relapse to alcohol-seeking the next day.

Strikingly, drinking remained suppressed for up to 14 days, the end point of the study. These results suggest that rapamycin erased the memory of alcohol for a long period, said Ron.

The authors said the study is an important first step, but that more research is needed to determine how mTORC1 contributes to alcohol memory reconsolidation and whether turning off mTORC1 with rapamycin would prevent relapse for more than two weeks.

The authors also said it would be interesting to test if rapamycin, an FDA-approved drug currently used to prevent organ rejection after transplantation, or other mTORC1 inhibitors that are currently being developed in pharmaceutical companies, would prevent relapse in human alcoholics.

“One of the main problems in alcohol abuse disorders is relapse, and current treatment options are very limited.” Barak said. “Even after detoxification and a period of rehabilitation, 70 to 80 percent of patients will relapse in the first several years. It is really thrilling that we were able to completely erase the memory of alcohol and prevent relapse in these animals. This could be a revolution in treatment approaches for addiction, in terms of erasing unwanted memories and thereby manipulating the brain triggers that are so problematic for people with addictions.”

Research reveals why some teenagers more prone to binge drinking

New research helps explain why some teenagers are more prone to drinking alcohol than others. 

The study, led by King’s College London’s Institute of Psychiatry (IoP) and published in Proceedings of National Academy of Sciences (PNAS)* provides the most detailed understanding yet of the brain processes involved in teenage alcohol abuse.

Alcohol and other addictive drugs activate the dopamine system in the brain which is responsible for feelings of pleasure and reward. Recent studies from King’s IoP found that the RASGRF2 gene is a risk gene for alcohol abuse, however, the exact mechanism involved in this process has, until now, remained unknown.

Professor Gunter Schumann, from the Department of Social, Genetic and Developmental Psychiatry (SGDP) at King’s Institute of Psychiatry and lead author of the study says: “People seek out situations which fulfill their sense of reward and make them happy, so if your brain is wired to find alcohol rewarding, you will seek it out. We now understand the chain of action: how our genes shape this function in our brains and how that, in turn, leads to human behaviour. We found that the RASGRF-2 gene plays a crucial role in controlling how alcohol stimulates the brain to release dopamine, and hence trigger the feeling of reward. So, if people have a genetic variation of the RASGRF-2 gene, alcohol gives them a stronger sense of reward, making them more likely to be heavy drinkers.”

*Paper reference:  Stacey, D. et al. ‘RASGRF-2 regulates alcohol-induced reinforcement by influencing mesolimbic dopamine neurone activity and dopamine release’ Proceedings of the National Academy of Sciences (PNAS)  2012

Alcohol Drinking Behavior Reduced By Inhibiting Brain Protein in Rodents

Decreasing the level of a key brain protein led to significantly less drinking and alcohol-seeking behavior in rats and mice that had been trained to drink, according to a study by researchers at the Ernest Gallo Clinic and Research Center at UCSF.

The scientists identified the protein, known as H-Ras, as a promising target for development of new medications to treat alcohol abuse disorders in humans.

The study, which was published on Nov. 7 in the Journal of Neuroscience, was recommended as being of special significance in its field by the Faculty of 1000, an online service that identifies great peer-reviewed biomedical research.

The researchers, led by Gallo investigator Dorit Ron, PhD, first demonstrated that alcohol intake significantly increased H-Ras activity in the animals’ nucleus accumbens, a brain region that in both rodents and humans is part of the reward system that affects craving for alcohol and other addictive substances.

They then showed that suppressing H-Ras levels in the nucleus accumbens with a targeted virus reduced alcohol consumption among mice that had been trained to seek out and drink alcohol in an animal model of binge drinking.

The researchers then administered FTI-276, an experimental compound that has been shown to inhibit H-Ras production, to binge-drinking rats. They observed a significant reduction in alcohol consumption after the compound was given.

The scientists also found that H-Ras inhibition reduced alcohol-seeking behavior among rats that had been trained to receive a drink of alcohol when they pressed a lever. When alcohol was withheld, rats that had received FTI-276 discontinued pressing the lever significantly sooner than rats that did not receive the compound.

Importantly, the rodents’ consumption of water, sugar solution, saccharine solution and quinine was not reduced when H-Ras was inhibited, indicating that H-Ras activity is specific to alcohol.