A malfunctioning enzyme may be a reason that binge
drinking increases the odds of alcoholism, according
to a study by scientists at the Stanford University
School of Medicine.
The scientists identified a previously unsuspected
job performed by the enzyme, ALDH1a1, in mice. The
discovery could help guide the development of
medications that extinguish the urge to consume
alcohol, said Jun Ding, PhD, assistant professor of
neurosurgery.
Ding is the senior author of the study, which will
be published Oct. 2 in Science. The study's lead
author is postdoctoral scholar Jae-Ick Kim, PhD.
Existing medications for treating alcoholism have
had mixed results. Disulfiram (Antabuse) and similar
substances, for example, work by inducing unpleasant
side effects -- including shortness of breath,
nausea, vomiting and throbbing headaches -- if the
person taking it consumes alcohol. "But these drugs
don't reduce the craving -- you still feel a strong
urge to drink," Ding said.
In the new study, Ding and his associates showed
that blocking ALDH1a1 activity caused mice's
consumption of and preference for alcohol to rise to
levels equivalent to those observed in mice that had
experienced several rounds of the equivalent of
binge drinking. Restoring ALDH1a1 levels reversed
this effect.
Previous studies have shown that mutations in the
gene for ALDH1a1 are associated with alcoholism, but
the reasons for this have been obscure.
A key finding in the new study is that in certain
nerve cells strongly implicated in addictive
behaviors, ALDH1a1 is an essential piece of a
previously unknown biochemical assembly line for the
manufacture of an important neurotransmitter called
GABA. Neurotransmitters are chemicals that bind to
receptors on nerve cells, promoting or inhibiting
signaling activity in those cells.
GABA is the brain's main inhibitory
neurotransmitter. It was previously thought that
GABA was made in mammalian brains only via a
different biochemical assembly line that doesn't
involve ALDH1a1.
While GABA is produced widely throughout the brain,
the novel GABA-production assembly line identified
by Ding's group was observed only in a group of
nerve cells known to play a powerful role in
addiction.
The new finding has potentially great clinical
significance because a drug that could increase GABA
synthesis through this alternative assembly line --
by boosting ALDH1a1 levels in the brain -- could
potentially restore the balance in neural circuitry
that's been thrown out of kilter by excessive
alcohol consumption without dangerously elevating
GABA levels elsewhere in the brain.
Another neurotransmitter substance, dopamine, is
famous among neuroscientists for its involvement in
modulating motion and motivation. Dopamine
supercharges the machinery of the brain's so-called
reward circuit, which is involved in all types of
addictive behavior from cocaine, morphine and
alcohol abuse to compulsive gambling.
The reward circuit is a network of nerve cells and
connections found in the brains of living creatures
from flies to humans and every animal in between. It
guides individuals' behavior -- and ensures species'
survival -- by offering pleasurable sensations as a
reward for eating, sleeping, having sex and making
friends. Key components of this circuit are fueled
by dopamine.
Until recently, neuroscientists widely assumed that
each type of nerve cell in the brain can release one
and only one neurotransmitter.
But in a study published in Nature in 2012, Ding,
then a postdoctoral scholar at Harvard Medical
School, and his colleagues demonstrated that
dopamine-producing nerve cells can manufacture and
release other types of neurotransmitters, too,
including GABA. These cells not only produce both
dopamine and GABA but release them simultaneously.
"We wondered what GABA is doing in there," Ding
said. "Why does one nerve cell need two
neurotransmitters?".
Ding also had another question. "All of us normally
encounter countless reward-inducing situations
without getting addicted," he said. "Every time I
publish a paper, my dopamine-producing nerve cells
go crazy, but I don't get addicted. Why not?"
To find out whether GABA in dopamine-producing cells
might have something to do with addiction, Ding and
his associates initially tried to examine GABA's
effects by blocking its production through the
conventional assembly line -- that is, the only one
known at the time -- while stimulating only
dopamine-producing cells in mice's brains. To their
surprise, these tried-and-tested methods failed to
reduce GABA levels in these cells or the
neurotransmitter's effects on nearby downstream
nerve cells. That was puzzling.
Curious, Ding began a literature search to see if
there were any other ways that biological systems
manufacture GABA. He learned that in plants, GABA
can be produced via a biochemical assembly line
quite separate from the common, previously known one
our brains use.
He found that one step in this alternative
GABA-manufacturing pathway is performed by a family
of enzymes, aldehyde dehydrogenases, that are better
known for being involved in the breakdown of
alcohol.
Ding also found that aldehyde dehydrogenases are
expressed not only in the liver, where most of the
alcohol we drink gets metabolized, but in some parts
of the brain that, to Ding -- whose professional
career has focused on the brain's dopamine-producing
nerve circuitry -- looked anatomically identical to
the dopamine-producing nerve cells that feed the
reward circuit. Ding's team verified that the
specific family member at work in those
dopamine-producing cells was ALDH1a1.
Using advanced laboratory methods to impair ALDH1a1
activity in mice, the scientists saw GABA levels in
dopamine-producing nerve cells drop, just as they
did when mice with normal ALDH1a1 activity underwent
repeated bouts of high alcohol intake -- the
equivalent of binge drinking. In behavioral tests,
the ALDH1a1-deficient mice showed the same increased
alcohol preference and intake as did otherwise
normal "binge-drinker" mice. These effects were
reversed by manipulations that raised ALDH1a1 levels
in the mice.
Ding said he thinks that GABA's co-release with
dopamine, and GABA's inhibitory character, may be
what prevents everyday pleasurable sensations from
causing most of us, most of the time, to become
addicted to the behaviors that produce them.
Mutations in ALDH1a1, he said, may predispose some
people to alcoholism by disabling this brake on our
reward machinery. His lab is now exploring whether
the same molecular mechanisms may be at work in
other forms of addiction.
For more information
Aldehyde dehydrogenase 1a1 mediates a GABA synthesis
pathway in midbrain dopaminergic neurons
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Stanford Medicine
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