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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
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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