What’s the News: Epidemiologists have long noticed that people with drug addictions often start out smoking cigarettes before moving on to harder stuff. Whether that’s because there’s something about cigarettes that makes people vulnerable to other drugs or because certain kinds of people are predisposed to addiction (or for some other reason entirely) is an open question, and the idea of so-called “gateway drugs” has been a controversial topic in addiction for years. Now, an elegant new study in mice has discovered a mechanism that could explain the gateway drug effect: nicotine actually changes the expression of genes linked to addiction.

How the Heck:

• First, the researchers (including biologist Denise Kandel and her Nobel laureate husband, Eric Kandel) gave mice nicotine to mimic the effects of cigarette addiction before giving them several injections of cocaine.
• Watching their behavior, the team saw that mice that had been given nicotine for many days returned again and again to locations where they had been given cocaine, far more—nearly double the frequency—than mice who had only received nicotine for 24 hours. In studies with drugs, this is a well-established sign of addiction.
• Opening up the brains of the mice, they found that the neuronal pathway that delivers cocaine’s rewards was much more strongly activated in mice that had had days of nicotine. This suggests that nicotine actually enhances the pleasure derived from cocaine.
• Looking deeper at the brain cells implicated in addiction and reward, they found that FosB, a gene whose expression helps cement addiction, was expressed at levels 74% higher than in mice who hadn’t had nicotine.
• Investigating how nicotine could have this effect, they discovered that it was acting at an epigenetic level—in other words, changing the chemical packing of DNA. Here’s how:
• When certain chemical tags are present on DNA, the double helix unfurls a bit, making it easier for the cellular machinery to get a hold of a gene, read off its code, and translate it into a protein. When mice were exposed to nicotine for many days, an enzyme that removes those tags and thus keeps certain genes out of circulation was knocked down. That was how nicotine caused FosB production, and thus, addiction, to go into overdrive.
• Importantly, the team found that this relationship was a one-way street: giving cocaine before nicotine did nothing. For this effect to take place, nicotine has to come first.

What’s the Context:

• The idea of gateway drugs has been discussed heatedly and at length, with many people pointing out that what most epidemiology studies show is correlation, not causation—just because people start out smoking cigarettes or marijauna and often move to harder drugs doesn’t indicate that cigarettes or marijauna caused the shift.
• While that’s certainly true, this particular study isn’t about observing trends in drug use—it’s a stringent investigation into what biological changes cigarettes might cause that could accelerate cocaine addiction later. It provides the first biological evidence for the gateway drug theory.

The Future Holds:

• This study will be a hard act to follow—it’s admirably thorough, progressing from animal behavior all the way down to the tags on DNA—but it should spur other addiction researchers to see whether nicotine has a similar effect when paired with other drugs. Also, alcohol and marijuana are frequently described as gateway drugs, and it will be interesting to see if they do anything similar to the brain.
• Outside the lab, the more we understand the biological mechanisms behind addiction, the closer we’ll come to figuring out a way to prevent or treat it. The researchers suggest that manipulating the enzyme that nicotine knocks down might be able to do something to reverse the effect.

Reference: Levine, et al. Molecular Mechanism for a Gateway Drug: Epigenetic Changes Initiated by Nicotine Prime Gene Expression by Cocaine. Science Translational Medicine, 2 November 2011: 107ra109

Image courtesy of SuperFantastic / flickr