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The alcoholic brain
Rockefeller scientists find that a familiar protein, tPA, plays a role in both alcohol dependence and symptoms of withdrawal
BY BETSY HANSON
For alcoholics, quitting drinking sometimes
comes with fatal consequences.
About five percent of alcoholics experience
delirium tremens during withdrawal — a disorder characterized
by tremors, seizures and hallucinations. Actor Ray Milland made the
DTs famous in his gritty, Academy Award-winning 1945 performance in
The Lost Weekend.
But what Milland didn’t know was that
the seizures occur because heavy consumption of alcohol — or
ethanol, the addictive component of beer, wine and liquor —
changes the brain. These changes allow an alcoholic to develop
tolerance to ethanol, but they also trigger the DTs when he
abruptly stops drinking.
Now Rockefeller University scientists, in
experiments with mice, have discovered a protein that regulates the seizures induced by ethanol
withdrawal. The protein, called tissue plasminogen activator, or
tPA, is the same factor that dissolves the blood clots that can
trigger heart attacks and strokes.
“We have found that tPA’s
interactions with certain brain receptors contribute to the
development of physical dependence on ethanol,” says Sidney Strickland, who directs Rockefeller’s Laboratory of
Neurobiology and Genetics. “Our new findings imply that
interfering with these interactions, with a drug for example, might
protect against alcohol-withdrawal pathologies in the brain.”
The study appears in the January 4 issue of Proceedings of the National Academy of Sciences.
Consuming alcohol slows down the transmission
of chemical messages in the brain. Ethanol molecules sit in a
receptor known as the NMDA receptor that would normally be occupied by a
stimulant — a neurotransmitter called glutamate — thus
preventing glutamate from delivering its message. When a person
drinks large amounts of ethanol over a long period of time, the
brain compensates by making more NMDA receptors on cells.
“The increase in NMDA receptors allows
the brain to function even under the depressive effect of
ethanol,” says Strickland. “But when alcohol
consumption stops, the brain is essentially too active. The person
in ethanol withdrawal feels anxious and agitated.”
Strickland and his colleagues knew from
earlier research that tPA interacts with NMDA receptors, in
particular a form of NMDA receptor with a binding site called NR2B.
“tPA is better known as a clot-buster,” explains
Strickland. “But it also functions in the central nervous
system. tPA is involved in making synapses work better, to
facilitate learning and memory.”
To investigate further the connection between
tPA and NMDA receptors in alcohol dependence, Strickland and his
colleagues studied two groups of mice that were genetically
identical except for the tPA gene: one group had the gene and made
the protein normally; the other did not have the gene for tPA, and
thus did not produce the tPA protein.
For 14 days the researchers put the mice on a
well-established regimen for mimicking the development of alcohol
addiction in humans. They fed all the mice a liquid diet that
included vitamins and a quantity of ethanol that increased from 2.3
to 10 percent of the diet volume over the course of the study.
Then, on the 15th day, they switched the mice to an alcohol-free
diet.
The normal mice suffered from seizures and
other symptoms of ethanol withdrawal that peaked six hours after
they stopped drinking the alcohol-containing diet. The mice that
lacked tPA also suffered the effects of ethanol withdrawal, but far
less severely.
“The action of ethanol in the brain is
complex,” says Robert Pawlak, the postdoctoral associate in
the Strickland laboratory who spearheaded the study.
“It’s important to stress that tPA-NMDA interactions
are not solely responsible for the development of physical
dependence to ethanol. Changes to other neurotransmitters and
receptors could explain why the mice in our experiments that lacked
tPA still developed moderate signs of ethanol
withdrawal.”
Strickland and colleagues also found that tPA
levels in certain brain structures — the hippocampus and the
amygdala — increased during the period when the mice were
ingesting increasing amounts of alcohol. This confirmed the
scientists’ suspicion that tPA plays a role in ethanol
dependence.
Next, after the mice stopped the alcohol diet,
the researchers injected tPA into the brains of mice that lacked
tPA. This led to an increase in seizures, confirming the link
between tPA and symptoms of ethanol withdrawal.
Finally, the researchers injected ifenprodil,
a drug that prevents tPA from binding specifically to the NR2B
subunit of NMDA receptors, into mice undergoing ethanol withdrawal.
The seizures and other symptoms abated.
“tPA sensitizes the nervous
system,” concludes Strickland. “That’s good while
ethanol is there, but bad once the ethanol is gone. Too much tPA
has pathological effects.”
The findings suggest that tPA pathways may be
potential drug targets and could lead to medicines that would help
alcoholics get through the critical first 72 hours after
withdrawal. “The next step will be to figure out in more
detail tPA’s mechanism of action,” says Strickland.
January 28, 2005
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