Intermittent binge drinking causes significant brain damage and
16 October 2012
A study of binge-drinking rodents suggests that knocking back
a few drinks every few days may swiftly reduce one’s capacity to control
alcohol intake. Scientists at The Scripps Research Institute (TSRI)
found signs of cognitive impairment in rats similar to that seen in
established alcoholism after the animals had only a few months of
intermittent access to alcohol.
The researchers linked the rats’ impairment to a small group of
neurons that inhibit “executive control” functions in the prefrontal
cortex of the brain. These neurons were unusually active in the
periods between drinking binges — and the more active they were, the
more the rats drank when they next had access to alcohol. The
finding, if confirmed in studies of humans, could lead to better
treatments, preventive approaches and diagnostic tests for problem
drinking and possibly other addiction-like behaviours.
“We suspect that this very early adaptation of the brain to
intermittent alcohol use helps drive the transition from ordinary
social drinking to binge drinking and dependence,” said Olivier
George, PhD, senior staff scientist at TSRI and lead author of the
“This research is giving us a window into the early development
of the addiction process,” said the study’s senior author, George F.
Koob, PhD, chairman of the Committee on the Neurobiology of
Addictive Disorders and co-director of the Pearson Center for
Alcoholism and Addiction Research at TSRI.
The new study appears online ahead of print in the Early Edition
of the Proceedings of the National Academy of Sciences the week of
October 15, 2012.
Binge drinking versus consuming a little every day
Scientists have long known that alcohol dependence and other
addictions feature striking changes in the brain. These include an
overactivity of stress-related circuits and a weakening of the
prefrontal executive control circuits that normally act as a brake
on emotional reactions and impulsive behaviours. What hasn’t been
understood is the sequence of neural events by which these changes
To find out more about these early events, Dr. George set up a
study of rats that had access to alcohol only three days per week
(Tuesday, Thursday and Saturday). Previous research had shown that
rats in this intermittent-access situation start out as modest
drinkers, but eventually turn into binge drinkers, consuming even
more than rats that have 24/7 access to alcohol.
“It’s like a lot of things in life that the brain perceives as
good — if it loses access to it, you feel bad, you get into a
negative emotional state, say a little bit frustrated, and so you
take more the next time you have access,” said Dr. George.
The team confirmed that the group of rats with intermittent
access drank markedly more alcohol, on average, than those with
continuous access after only six weeks. In tests conducted a few
weeks later, during “dry” intervals between drinking bouts, the
binge drinking rats scored poorly on measures of working memory, an
essential element of executive control.
Tests of their brain tissue
also revealed that during these withdrawal periods — when the
animals would have been expected to be craving alcohol — the
prefrontal cortex seemed relatively disconnected from the structures
it is meant to regulate, such as the emotion-related amygdala.
“We normally see such changes in the brains of humans or other
animals that are highly dependent on alcohol, but here we found
these changes in the rats after only a few months of intermittent
alcohol use,” said Dr. George.
Remarkably, these impairments did not appear at all in the
drink-every-day rats, whose alcohol intake remained stable. “They
just drink a bit like the French way, the equivalent of a couple of
glasses of wine every day, and they’re fine,” said Dr. George. “They
As for the binge-drinking rats, their cognitive impairment went
away if they were kept off alcohol for about two weeks — but the
impairment would return if they simply drank again. “One can see the
vicious cycle here,” said Dr. George. “They drink to restore normal
prefrontal function, but ultimately that leads to even greater
“This process would be of particular concern in adolescents and
young adults, in whom the prefrontal cortex isn’t even fully
developed,” Dr. Koob said.
Changes in the brain
Further tests suggested that the immediate cause of the
impairment in the binge-drinking rats was a small population of
medial prefrontal cortex neurons known as GABA interneurons. These
neurons are known to serve as “dimmer switches” for nearby
excitatory neurons within the medial prefrontal cortex.
In the binge-drinking rats, the GABA neurons were unusually
active during periods of impairment. In general, the more active
these GABA neurons are, the less the prefrontal cortex is able to do
its primary job of exerting executive control over other, relatively
impulse-driven brain regions.
The team also found hints that the GABA interneurons in the
binge-drinking rats may be activated by adjacent prefrontal neurons
that secrete the stress neurotransmitter CRF. This molecule is
already closely associated with alcoholism. In alcohol-dependent
rats, and likely in human alcoholics too, abstinence triggers a
flood of CRF in the central nucleus of the amygdala — creating a
feeling of anxiety that typically can only be alleviated by drinking
again. “Now we see that that this early dysregulation of the
prefrontal cortex by binge drinking may also be driven by CRF,” Dr.
The Koob lab and other teams of addiction researchers have begun
to investigate CRF-blocking drugs as potential treatments for
established alcohol dependence. The new results, Dr. Koob said,
raise the possibility that such drugs might also work to prevent
alcohol dependence. CRF may turn out to be a good target for
diagnostic tests, too.
“When someone develops a molecule that binds to CRF with high
enough specificity, so that we can measure CRF activity in the
living human brain with a PET scan, we might then have a good way to
detect if someone is alcohol-dependent or on the path to
dependency,” he said.
George O, et al. Alcohol withdrawal activates GABA and
corticotropinreleasing factor (CRF) neurons in the medial prefrontal
cortex (mPFC) that predict cognitive impairment and escalation of
alcohol intake. Proceedings of the National Academy of