Seizures are the most life-threatening, as well as disconcerting, symptoms of withdrawal in people who are alcoholics and who abruptly stop drinking. Heavy consumption of alcohol, or ethanol, the substance in beer, wine and liquor that is addictive, leads to changes in the brain. These changes allow an alcoholic to develop tolerance to ethanol. But they also trigger seizures and other symptoms of delirium tremens when alcohol consumption stops.
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.
The Rockefeller scientists' finding suggests that drugs targeting tPA might prevent the seizures as well as other impairing effects of ethanol withdrawal. The results appear in the Jan.3 online issue of Proceedings of the National Academy of Sciences.
"What we have found is that tPA's interactions with certain brain receptors contribute to the development of physical dependence on ethanol," says Sidney Strickland, Ph.D., head of Rockefeller's Laboratory of Neurobiology and Genetics. "Our new findings imply that interfering with these interactions might protect against alcohol-withdrawal pathologies in the brain."
Nearly 14 million Americans abuse alcohol or are alcoholic. Without access to alcohol they go into withdrawal, which can include insomnia, tremor, muscle rigidity, hallucinations and seizures. These symptoms, often called delirium tremens, kill about 5 percent of the people who develop them.
Consuming alcohol slows down the transmission of chemical messages in the brain. Ethanol molecules sit in a receptor (called 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 it also leads to the symptoms of withdrawal.
"An analogy is driving a car and trying to maintain a speed of 30 miles per hour," explains Strickland. "Ingesting alcohol is like stepping on the brake. To maintain your speed, you need to press harder on the gas, which in the brain means making more NMDA receptors. Then if the brake is suddenly released, the car goes too fast. This is what happens with delirium tremens. When alcohol consumption — the brake — stops, the brain is essentially too active. The person in ethanol withdrawal feels anxious and agitated, and may have tremors or seizures."
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, used to treat heart attack or stroke patients," 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 showed some — but much less severe — effects of ethanol withdrawal.