Saturday, May 16, 2009

The Alcoholic Rats of Dr. Li.

Excerpt from chapter 1 of The Chemical Carousel.

In the early 1990s, it was safe to say that Dr. Ting-Kai Li was in possession of the largest and most famous collection of alcoholic rats in the world.

Housed in a laboratory near Dr. Li’s office at Indiana University, the “P-line” of rodents were freely self-administering the body-weight equivalent of one bottle of whiskey a day for a 155-pound man; a blood alcohol concentration that would have gotten them arrested on any highway in America. The P-line rats were seriously addicted to ethanol, the purified form of booze known outside the laboratory as grain alcohol, or white lightning.

“It’s actually the only line that’s been well developed in the world,” Dr. Li told me at the time, with justifiable pride. “And it has been developed through genetic selection for alcohol preference.” In other words, Dr. Li did not teach these animals to drink. He didn’t have to.

Dr. Li, who was until recently the Director of the National Institute on Alcohol Abuse and Alcoholism (NIAAA), which is the alcoholism wing of the National Institutes of Health (NIH), made it sound easy: “You take a stock with some genetic heterogeneity in it, and then you test it for drinking behavior, and there will be, say, two or three out of a hundred that like to drink, so you take those, and you breed them. And the ones that don’t like to drink, you breed those, and within ten generations you start to have a very good separation between drinking scores.”

Why would a rat drink alcohol, and why would anybody care? When I first spoke with Ting-Kai Li, the lack of suitable animal models of alcoholism and addiction was all too apparent. Without suitable strains of test animals, most genetic and neurobiological research would take centuries, and would involve ethical questions about human testing far stickier than the questions raised by the animal rights movement. Animal models are one of the primary pathways of discovery available to neurobiologists and other researchers.

The precisely spoken, self-effacing Dr. Li, along with neurobiology professor Dr. William McBride and their co-workers at Indiana University, were never really in the business of teaching rats to drink. They were in the business of discovering ways to make them stop.

To be like human alcoholics, the rats must also demonstrate both an increased tolerance to the effects of the drug, and the onset of physical dependence as manifested by withdrawal symptoms. And they do. The P-line rats develop tolerance, and they show acute withdrawal symptoms when researchers cut off their supply. The rats suffer tremors, seizures, and a rodent version of delirium tremens. They fall down a lot. They are also quick to avail themselves of a little “hair of the dog.” After a period of abstinence, they take alcohol again to relieve the withdrawal symptoms.

The P-line rats met every definition of alcoholism anyone could imagine, and the cause of their alcohol addiction appears to be strictly genetic. What was happening with the P-line rats was not explainable by resorting to arguments about simple learned behavior.

“How do you explain this difference?” said Dr. Li, all those years ago. “My explanation is that there are genetic differences among different individuals. You’re making the assumption that you expose them to the same environment, the same environmental influences, and yet they behave differently in terms of addiction.”

Today, we can safely say that Dr. Li’s hypothesis has proven to be true.

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