Two elements make an iconic shot from the 1983 movie Scarface instantly recognizable: Al Pacino and his mountain of cocaine. What’s often forgotten is the tumbler of whiskey, sitting to his right.

As in many movies featuring cocaine, his alcohol abuse is treated with less gravity than his cocaine habit, but groundbreaking research published Wednesday in Science Advances shows that the two vices are intertwined.

In the study, scientists show that having a history of alcohol use increases the chances of cocaine addiction occurring later on in life.

What the Columbia University Medical Center scientists behind the study, led by psychiatrist Edmund Griffin Jr., M.D., Ph.D., were trying to figure out was how the “gateway drug” hypothesis actually works. While “gateway drug” has become a ubiquitous term to describe mild substances that lead to harder drugs, it hasn’t been clear how those first-time drugs make users vulnerable.

“The mechanism was always a big question of social vs. biological,” Griffin tells Inverse. He says some scientists think it depends on whether a potential user is hanging out with people who use drugs, while others think some people are genetically predisposed to drug use.

Alcohol primes the brain for cocaine addiction

“In our study, you don’t have those cofounding factors,” he says. In the paper, Griffin and his team clearly show a biological mechanism for how alcohol primes the brain to become addicted to cocaine.

Using rats, he and his team set up a simple experiment in which rats pushed a little lever to access as much cocaine as they wanted. Some of those rats had been given 10 percent alcohol for 10 days before they started the cocaine phase of the experiment, while the other rats stayed sober.

The rats who’d been exposed to alcohol soon began demonstrating the classic signs of addiction: persistent, uncontrollable drug use, even in the face of punishment.

It quickly became clear that the rats who’d been “primed” with alcohol were becoming addicted more intensely: When the experimenters tweaked the setup so that no cocaine came out when the levers were pressed, the alcohol-primed rats demanded cocaine much more furiously than their control counterparts. On average, the control rats pressed the lever 18 times, while the alcohol-primed rats pressed it 58 times.

The alcohol-primed rats also became more determined drug seekers. Even when pressing the lever delivered both cocaine and a small electric shock, they continued to be “resistant to punishment,” the researchers write. At the highest level of shock intensity — 0.3 mA — the alcohol-primed rats still managed to obtain 29 percent of the total cocaine they’d previously received.

Clearly, alcohol had acted as a gateway drug for these rats, so the researchers looked into the brains of other rats who had been exposed to the same alcohol regime to see what was different on the molecular level.

They focused on the nucleus accumbens, “one of the key brain regions that helps mediate drug-based reward,” Griffin explains. There, they noticed that two proteins from the histone deacetylase family, called HDAC4 and HDAC5, had begun to break down.

“HDACs sit inside the cell’s nucleus, which is like D.C. — where all the decisions are made,” he says, explaining that they prevent new proteins from being made in response to changes in environment. If they’re not around to do that, they can’t act as the “brakes” on the reward circuitry of the brain, which is what’s thought to lead to more compulsive reward seeking through drug use.

However, it appears that a substance is a gateway drug only if it’s used repeatedly: The researchers point out that the protein breakdown only happened in rats that had received the full 10-day exposure to alcohol; in rats who just had a two-day binge, the nucleus accumbens appeared to be normal. To the researchers, this was evidence that using a drug for only a short period of time doesn’t have as serious an effect on addiction as long-term drug use.

Alcohol is the most ubiquitous substance on the list of gateway drugs, which also includes nicotine and, controversially, marijuana.

“This study really does then ask the question — are these mechanisms similar for other drugs like marijuana?” Griffin wonders.

Whether other gateway drugs will have the same effects as alcohol on the brain remains to be seen. But if they are similar, scientists will have a concrete method for defining whether a substance is actually a gateway drug.

Griffin’s research shows a clear biological basis for the mechanisms behind the gateway drug theory, which suggests that medical interventions — say, a treatment that acts directly on the neuron’s HDAC proteins — are possible. “It points our attention to some of the earlier stages and the developmental sequence of addiction from a public health standpoint,” he says.

However, he emphasizes that addiction is a complicated problem that science alone can’t treat. “It has to be treated from both a medical, social, and a public health perspective,” he says.

If you liked this article, check out this video where a drunk scientist explains what alcohol does to your brain.