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Researchers target withdrawal symptoms in drinkers (9/3/97)

Drinkers may consider themselves moderate consumers of alcohol, but if they drink on a daily basis, say, after work or with dinner, and then not again until the next day, pharmacologists now know that their brains are constantly undergoing withdrawal symptoms.

A laboratory model developed at The University of Texas Health Science Center at San Antonio mimics the effect of repeated alcohol withdrawal on brain function and will be reported at the October 25-30 meeting in New Orleans of the Society of Neuroscience.

Pharmacology researchers Maharaj Ticku, PhD, and Xian-Jue Hu, MD, have developed a laboratory model to study the effects of repeated alcohol withdrawal on brain function using nerve cells from the brain's cortex.

"Chronic use of alcohol leads to tolerance and physical dependence," reports Dr. Ticku. "During withdrawal, humans and animals exhibit withdrawal symptoms including increased anxiety, brain excitation, dysphoria (depression and unrest), and in some cases, seizures. There is evidence that intermittent or repeated exposure to alcohol produces a kindling-like phenomenon, that is, development of a permanent state of seizure susceptibility. This phenomenon may be responsible for alcohol withdrawal symptoms including delirium and seizures and is relevant to human alcoholism."

The researchers observed that repeated alcohol withdrawal produces changes in the properties of a subtype of glutamate receptor in the brain called an N-methyl-D aspartate receptor (NMDA). The NMDA receptors are involved in a variety of physiological processes, including maintenance of brain excitability, neuronal (nerve cell) development, learning and memory. Dr. Ticku says, "We and others have shown that the NMDA receptors are involved in many of alcohol's effects in brain. Our studies demonstrate for the first time that repeated ethanol (a type of alcohol) withdrawal produced upregulation of NMDA receptors in the *in vitro* (laboratory) model of cortical neurons, and this persisted for at least 7 days following last alcohol exposure. This implies that there were more NMDA receptors formed, and this upregulation persisted even though there was no alcohol in the brain.

"We also observed that this increase in the number of NMDA receptors was due to a selective increase in the gene expression of some of these receptors," Dr. Ticku says. "These are important findings and indicate that repeated alcohol intake and withdrawal, which parallels human alcohol consumption, produces changes in an important brain chemical receptor system.

"These findings thus have relevance to human alcoholism and suggest that NMDA receptors may play a role in alcohol's effects including withdrawal symptoms, loss of memory, neuronal loss and the reported kindling-like phenomenon observed in humans and animals."

Further studies are in progress which the researchers believe will eventually contribute to rational development of drug therapy for alcohol-related problems.

Contact: Mike Lawrence (210) 567-2570