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.
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.
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 alcoholic
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