The idea of a “gateway drug” may sound like a throwback to the “Just say no” era. But new research offers fresh evidence that alcohol and nicotine — two psychoactive agents that are legal, ubiquitous and widely used during adolescence — ease the path that leads from casual cocaine use to outright addiction.

About 21 percent of those who use cocaine on an occasional basis wind up taking the drug compulsively, experts estimate. That leads researchers who study drug addiction to ask: What sets those addicts apart from their peers?

Perhaps alcohol and nicotine are the missing link.

When rats were primed with either substance, they experienced durable chemical changes in their brains that could make them more susceptible to cocaine dependency, according to a study published Wednesday in Science Advances.

Those changes were etched into the machinery that turns genes on and off in the reward centers of the brain, creating a “permissive environment” for addiction, the study authors wrote.

Indeed, when rats were allowed to drink alcohol every day for nearly two weeks — a considerable length of time in the lifespan of a rat — and then given access to a dose of cocaine, they engaged in drug-seeking behavior with such determination that they were barely deterred by painful electric shocks.

The experimental results help “cement the validity of the gateway hypothesis,” said Dr. Nora Volkow, director of the National Institute on Drug Abuse, which funded the study.

The findings also suggest that researchers might be better off focusing on “gateway mechanisms” — the common molecular pathways through which some substances can influence future addiction — than on “gateway drugs,” she added.

To be sure, even rats who had never tried alcohol took to cocaine when given the chance, pressing a lever to administer themselves doses. And as researchers made rats work harder for a dose of cocaine, both teetotalers and alcohol-primed rats stepped up their efforts. Many rats continued to press the lever — even when doing so resulted in increasingly stronger electrical shocks.

But alcohol made a big difference.

In experiments led by psychiatrist Dr. Edmund Griffin, neurobiologist Dr. Eric R. Kandel and epidemiologist Denise Kandel, all of Columbia University, a group of rats were allowed access to alcohol for two hours a day over 11 days. Then they gained access to cocaine for various stretches over the next 32 days.

As researchers required more work for the cocaine, the alcohol-treated rats pressed a lever an average of 563 times — much more than the average 310 lever presses mustered by another group of rats with no alcohol history. Days after cocaine administration had ceased, the rats exposed to alcohol pressed the cocaine lever 58 times, on average — far more than the 18 lever presses averaged by the rats that were not primed with alcohol, according to the study.

The two groups of animals also reacted differently to the painful shocks meant to deter them from using cocaine. Among rats who’d gotten no alcohol, the shocks prompted most to stop pressing the lever pretty quickly, with only 14 percent continuing to do so. However, among rats primed with alcohol, most were willing to endure several sets of shocks before giving up, and 29 percent continued to press the lever even when doing so brought on the strongest shocks researchers gave.

It wasn’t just their drug-seeking behavior that was different; the researchers observed a wide range of chemical differences in their brains as well. Many of those changes were seen inside the nucleus accumbens, a key node in the brain’s reward-seeking network. And they took place in the epigenome, the chemical messaging system that turns genes on and off in response to changing needs or circumstances.

Scientists had previously seen that when the specific brain changes wrought by alcohol were induced by other means, the result was a higher propensity to addiction. The results of earlier work by the same research group show that prolonged nicotine use can do the same thing.

“We certainly suspected” that both alcohol and nicotine were implicated in addiction to illegal drugs, Volkow said; population studies have clearly suggested as much. “But the finding of this common gateway pathway between nicotine and alcohol opens up new avenues in prevention research,” she said.

Teen smoking has dropped to its lowest level since tracking began 41 years ago, with 7 percent of kids in 8th, 10th and 12th grades saying they’ve smoked in the last month. But the proportion of high school students who say they’ve drunk alcohol in the last month is about 33 percent, with 18 percent acknowledging a session of binge drinking in that period.

Volkow added that the study raises the question “whether marijuana, which is also considered a gateway drug, shares these properties.”

University of Pennsylvania neuroscientist John Dani, who researches addiction but was not involved in the new study, called the findings intriguing on many levels.

By changing the order in which humans usually try cocaine and alcohol, the authors showed there may be something uniquely “priming” about using alcohol first, Dani said.

That message is particularly important for adolescents, who should understand that drinking and smoking early in life may cause lasting brain changes that make addiction more likely down the line.

The fact that the experiments were conducted on rats, not people, does not diminish the significance of their results, Dani added.

“A rat is not necessarily a good model for the behavior of a human, but their neurons do things very similar to our neurons,” he said. “We have those same enzymes and same epigenetic processes in our neurons, and that’s where this has real value. At this molecular level, they’re very similar to us.”

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