For First Time, Researchers Describe Molecular Mechanism for a 'Gateway Drug'—Nicotine

by Kayt Sukel

November 22, 2011

A few years ago, I attended an open Alcoholics Anonymous meeting to support a friend in recovery. During a brief break, it was impossible not to notice how many attendees rushed outside for a cigarette. Epidemiological studies have long linked smoking to other forms of addiction—but, to date, they have been unable to establish any direct biological connections. A study published in the Nov. 2 issue of Science Translational Medicine, however, has now demonstrated how nicotine may accelerate both the cellular and epigenetic processes underlying addiction, providing the first biological explanation of a “gateway” drug.

A gateway to harder drugs

The Drug Abuse Resistance Education (D.A.R.E.) organization defines a gateway drug as one “that opens the door to the use of other, harder drugs.” Common gateway drugs include tobacco, alcohol and marijuana—substances that are both inexpensive and easily obtained by most people. But while many epidemiological studies have correlated early use of tobacco or marijuana with later use of hard drugs like cocaine or heroin, researchers have been unable to identify any direct links.

“Science is driven by the technology and tools available. You cannot look where there is darkness, where there is no way of exploring,” says Nora Volkow, director of the National Institute on Drug Abuse (NIDA). “In the past, epidemiological studies were not able to pay sufficient attention to the biology involved because they did not have the tools to explore it. That is changing now.”

So when Denise Kandel, a professor of sociomedical sciences at Columbia University’s Mailman School of Public Health, learned more about some research on cocaine and learning led by her husband, famed Columbia University neuroscientist Eric Kandel, she thought the biological tools to examine the relationship between nicotine and cocaine addiction might finally be available. To study the question of the gateway sequence, the two embarked on their first scientific collaboration in 55 years of marriage.

Priming the brain for addiction

To test nicotine’s effects as a gateway drug, the Kandels and their colleagues exposed mice alternately to nicotine and cocaine and then looked at the animal’s behavior as well as changes to synaptic plasticity in the striatum, a dopamine-rich area of the brain that has long been linked to reward processing and addiction. They found that the animals that received nicotine both just before and during cocaine administration showed not only a bigger behavioral response to the harder drug (as measured by locomotor sensitization and conditioned place preference tests), but also significant reduction in long-term potentiation in striatal neurons. These effects were only seen with the nicotine pre-treatment—and then only when cocaine was administered at the same time as the nicotine.

“What we found is that nicotine stimulates the synaptic connectors in the brain involving the dopaminergic circuitry, inhibiting it,” says Eric Kandel. “And nicotine pretreatment, having that nicotine prior to cocaine, enhances that effect dramatically.” (Eric Kandel, who won the 2000 Nobel Prize in Physiology or Medicine, is also a vice-chairman of the Dana Alliance for Brain Initiatives.)

An epigenetic mechanism

Epigenetics is a blossoming field in neurobiology that looks at the ways that the environment can directly influence genes by either increasing or decreasing their activity. One way it does so is a process called acetylation. In each cell, DNA is wrapped around a core of alkaline proteins called histones. These proteins have long tails that sometimes stick out of their double-helix shell. Through natural cell chemistry, acetyl groups can attach to those tails, creating space between DNA strands and upping production of the associated protein. The enzyme histone deacetylase, however, removes those acetyl groups, decreasing gene transcription.  

When the Kandels and their colleagues looked at transcriptional activation of FosB, one of the genes linked to addiction, they found that the nicotine pre-treatment inhibited histone deacetylase, dramatically increasing transcription of FosB proteins in the striatum.

“Acetylation is necessary for gene activation. Deacetylation shuts the gene off. We found that deacetylation is inhibited by nicotine. We could actually use an off-the-shelf inhibitor drug and simulate exactly what nicotine does at every single point,” says Eric Kandel. “It appears that nicotine is a very powerful precursor and starts this gateway sequence for addiction in the brain by inhibiting a shut-off mechanism for FosB. “

Going back to the epidemiology

While many epidemiological studies have shown that smoking and cocaine addiction are related, none had previously looked at exactly how addicts were using nicotine in relation to their cocaine abuse. After she saw the mouse test results, Denise Kandel went back to epidemiological data sets to see if addicts did smoke cigarettes and use cocaine concurrently.

“The rates of addiction to cocaine were twice as high among those who were actually smoking at the time they started using cocaine,” she says. “It was nice confirmation of the mouse experiment. It would seem exposure to nicotine while using cocaine not only increases the risk of continuing to use cocaine but of becoming addicted.”

Starting a new field

Both the biological and the epidemiological communities have hailed this study as a major breakthrough. Volkow, at a National Institutes of Health press conference at the Neuroscience 2011 conference, called the paper “transformative.” 

“This is the first study that documents the mechanism of a gateway theory for addiction biologically,” she said. “It provides evidence that indeed early exposure with drugs can prime your brain to the rewarding effects of other drugs.”

Volkow hopes researchers will do more such integrative work on aspects of drug addiction. And she hopes that the Kandels will expand their model, testing these effects on adolescent instead of adult mice as well as with other potential gateway drugs.

The Kandels and colleagues are currently using the same model to look at alcohol as a gateway to cocaine addiction. And Eric Kandel is hopeful that this study will pave the way for more translational epidemiology studies.

“We need to be doing more of this. There is a lot of good epidemiological data out there,” he says. “And more than just pointing out this gateway sequence, I hope that this paper calls attention to the fact that one can really take epidemiological findings and explore them in molecular detail. With luck, this work will stimulate a whole new field.”