Scientists Pinpoint Brain Region That May Be Center of Alcohol Addiction...

Researchers map out a cellular mechanism that offers a
biological explanation for alcoholism, and could lead to
treatments

You can lead a lab rat to sugar water, but you can’t make him
drink—especially if there’s booze around.
New research published Thursday in Science may offer
insights into why some humans who drink alcohol develop an
addiction whereas most do not. After caffeine, alcohol is the
most commonly consumed psychoactive substance in the
world. For the majority of people the occasional happy hour
beer or Bloody Mary brunch is where it stops. Yet we all know
that others will drink compulsively, despite whatever
consequence or darkness it brings.
The new research confirms earlier work showing this is true for
rats; but it takes things a step further and supports a study
design that could help scientists better understand addiction
biology, and possibly develop more effective therapies for
human addictive behaviors. Led by a team at Linköping
University in Sweden, the researchers found that when given a
choice between alcohol and a tastier, more biologically
desirable sugar substitute, a subgroup of rats consistently
preferred the alcohol. The authors further identified a specific
brain region and molecular dysfunction most likely responsible
for these addictive tendencies. They believe their findings and
study design could be steps toward developing an effective
pharmaceutical therapy for alcohol addiction, a kind of
treatment that has eluded researchers for years.
A taste for sweetness is evolutionarily embedded in the
mammalian brain; in the wild, sugar translates into fast
calories and improved survival odds. For the new study, 32
rats were trained to sip a 20 percent alcohol solution for 10
weeks until it became habit. They were then presented with a
daily choice between more alcohol or a solution of the
noncaloric sweetener saccharine. (The artificial sweetener
provides sugary-tasting enticement without the potential
confounding variable of actual calories.) The majority of rats
vastly preferred the faux sugar over the alcohol option.
But the fact that four rats—or 12.5 percent of the total—stuck
with the alcohol was telling to senior author Markus Heilig,
director of the Center for Social and Affective Neuroscience at
Linköping, given the rate of alcohol misuse in humans is
around 15 percent. So Heilig expanded the study. “There were
four rats who went for alcohol despite the more natural reward
of sweetness,” he says. “We built on that, and 600 animals
later we found that a very stable proportion of the population
chose alcohol.” What’s more, the “addicted” rats still chose
alcohol even when it meant receiving an unpleasant foot
shock.
To get a better sense of what was going on at a molecular
level, Heilig and his colleagues analyzed which genes were
expressed in the rodent subjects’ brains. The expression of
one gene in particular—called GAT-3 —was found to be greatly
reduced in the brains of those who opted for alcohol rather
than saccharine. GAT-3 codes for a protein that normally
controls levels of a neurotransmitter called GABA, a common
chemical in our brains and one known to be involved in
alcohol dependence.
In collaboration with co-author and University of Texas at
Austin research scientist Dayne Mayfield, Heilig’s team found
that in brain samples from deceased humans who had
suffered from alcohol addiction, GAT-3 levels were markedly
lower in the amygdala—generally considered the brain’s
emotional center. One might assume that any altered gene
expression contributing to addictive behaviors would instead
manifest in the brain’s reward circuitry—a network of centers
involved in pleasurable responses to enticements like food,
sex and gambling. Yet the decrease in GAT-3 expression in
both rats and humans was by far strongest in the amygdala.
“Figuring out the reward circuitry has been a fantastic success
story, but it’s probably of limited relevance to clinical
addiction,” Heilig says. “The rewarding effect of drugs happens
in everybody. It’s a completely different story in the minority
of people who continue to take drugs despite adverse
consequences.” He believes altered activity in the amygdala
makes perfect sense, given that addiction—in both rats and
humans—often brings with it negative emotions and anxiety.
Much previous addiction research has relied on models in
which rodents learn to self-administer addictive substances,
but without other options that could compete with drug use. It
was French neuroscientist Serge Ahmed who recognized this
as a major limitation to understanding addition biology given
that, in reality, only a minority of humans develops addiction
to a particular substance. By offering an alternative reward
(that is, sweet water), his team showed only a minority of rats
develop a harmful preference for drug use—a finding that has
now been confirmed with several other commonly abused
drugs.
Building on Ahmed’s concept, Heilig added the element of
choice to his research. “You can’t determine the true reward of
an addictive drug in isolation; it’s dependent on what other
options are available—in our case a sugar substitute.” He says
most models that have been used to study addiction, and to
seek ways to treat it, were probably too limited in their design.
“The availability of choice,” he adds, “is going to be
fundamental to studying addiction and developing effective
treatments for it.”
Paul Kenny, chair of neuroscience at Icahn School of Medicine
at Mount Sinai, agrees. “In order to develop novel therapeutics
for alcoholism it is critical to understand not just the actions
of alcohol in the brain, but how those actions may differ
between individuals who are vulnerable or resilient to the
addictive properties of the drug,” he says. “This Herculean
effort to impressively map out a cellular mechanism that likely
contributes to alcohol dependence susceptibility will likely
provide important new leads in the search for more effective
therapeutics.” Kenny was not involved in the new research.
Heilig and his team believe they have already identified a
promising addiction treatment based on their latest work, and
have teamed up with a pharmaceutical company in hopes of
soon testing the compound in humans. The drug suppresses
the release of GABA and thus could restore levels of the
neurotransmitter to normal in people with a dangerous taste
for alcohol.