By David N. Leff

Are drug addicts born or made?

In other words, is addiction inherited in their nature, or acquired in their nurture?

Inasmuch as there is no effective treatment for cocaine addiction, the possible existence of a gene that fosters the habit, unbreakable in some, is getting a lot of attention from neuroscientists.

Initially the researchers focussed on dopamine, the neurotransmitter in the brain responsible for the rewarding euphoria that marks a cocaine high. But lately, another cerebral player, the serotonin neurotransmitter, has come on the scene. Cocaine, it turns out, has a higher affinity for serotonin (a.k.a. 5-hydroxytryptamine, or 5-HT) than it does for dopamine.

Serotonin has a lot to answer for in the brain and body. It's linked to such diverse torments as anxiety, depression, sexual dysfunction, digestive ailments, migraine headaches, sleep disorders.

No wonder Indianapolis-based Eli Lilly & Co. sold $2 billion worth of Prozac, the oral antidepressant, in 1995. Prozac (fluoxetine hydrochloride) strongly inhibits the uptake of serotonin in that neurotransmitter's target brain cells. (See BioWorld Today, Nov. 5, 1996, p. 1.)

At least 14 receptor molecules honcho the uptake of serotonin, in its multifarious activities. Dopamine makes do with four receptors.

Some years ago, neurobiologist René Hen, at Columbia University, in New York, created a knockout mouse deprived of the gene for 5-HT1B, a subunit of the serotonin molecule's first receptor. He and his co-authors found that these knockout rodents had a strong bent for alcohol addiction. (See BioWorld Today, Sept. 16, 1996, p. 1.)

Now Hen reports a similar leaning in these animals toward cocaine. His paper in the current issue of Nature, dated May 14, 1998, bears the title: "Increased vulnerability to cocaine in mice lacking the serotonin-1B receptor."

An accompanying editorial by molecular pharmacologist Francis White described the Columbia findings as "the first definitive evidence for the involvement of a specific serotonin receptor in processes that may underlie cocaine addiction." White is at the Finch University of Health Sciences/Chicago Medical School, in North Chicago, Ill.

Coke Hungry Knockouts Doubled Their Fix

Hen's mice were first sent to cocaine boot camp, where they, and a cohort of normal wild-type littermates, were trained to self-dose on the drug by pressing a lever. One press, one fix, mainlined by a catheter into their bloodstream. After the rodents had mastered this routine, the co-authors made it harder; they progressively ratcheted up the number of presses it took to get a shot of the good stuff.

The coke-eager knockouts earned twice as many fixes as their normal controls. Short-changed of the serotonin receptor gene, they pressed their levers 25 times on average, for eight addiction-reinforcing injections; controls — presumably less addicted — dropped out after nine such efforts.

When saline solution instead of drug went into the catheters, both contingents — nobody's fools — quit pressing.

Besides its euphoric ecstasies, cocaine also stimulates psychomotor behavior. To test this effect, the team placed both kinds of mice in a 40-square-centimeter open area, right after giving them a single shot of saline or cocaine. Then they measured the animals' running, sniffing, rearing and head-weaving — all typical of cocaine's effects. Comparison with wild-type performance on escalating drug doses indicated the null-mutation knockouts were pre-sensitized to the narcotic.

At this point, the co-authors went from behavioral to molecular analysis of that sensitization. They examined neurochemical changes in the brains of both knockout and normal mice, and found in knockouts heightened levels of immediate early proteins related to the c-fos gene. These antigens are increased by chronic exposure to cocaine, and are presumably critical for both its locomotor and rewarding effects. (See BioWorld Today, Sept. 16, 1997, p. 1.)

"More and more evidence suggests that an individual's genetic makeup is a major factor in determining his or her vulnerability to drug addiction." So said Alan Leshner, director of the National Institute on Drug Abuse, which partly funded Hen's research. "Research studies such as this," Leshner added, "move us closer to identifying the specific genes involved in addiction, and closer to new strategies for drug abuse prevention and treatment." *