Nicotine sensitizes the mouse brain to the addictive effects of cocaine, according to recent NIDA-supported research. If the findings carry over to people, they would suggest that preventing youths from smoking might reduce their vulnerability to cocaine abuse and addiction, and cocaine-dependent individuals might ease their path to recovery, by quitting smoking.
Drs. Amir Levine, Eric R. Kandel, and Denise Kandel conducted the research with colleagues at Columbia University. In their experiments, mice that were chronically exposed to nicotine exhibited more addiction-like behaviors and addiction-related brain changes when subsequently exposed to cocaine than mice that had never had nicotine. The researchers identified a nicotine-induced epigenetic effect in the brain’s reward system that could underlie the nicotine-exposed animals’ heightened responses to cocaine (see box).
These findings may help settle a theoretical controversy. Two rival hypotheses have been advanced to explain why smokers are more likely than nonsmokers to abuse other drugs. The Columbia group’s results accord with the “gateway” hypothesis, which proposes that a person’s initial use of an addictive substance physiologically sensitizes his or her brain to the rewarding and addictive effects of other substances.
The alternative to the “gateway” hypothesis posits that human drug use patterns simply reflect that the same genetic and environmental factors that influence people to take a first drug also promote abuse of other drugs. Although genetic and environmental factors surely play a role in those patterns, they are highly unlikely to have contributed to the new results, which were obtained with laboratory animals that were all genetically similar, raised together, and subjected to the same manipulations.
Gravitating to Pleasure
The Columbia group used a common laboratory protocol to show that nicotine increases animals’ sensitivity to the rewarding effects of cocaine. Called conditioned place preference , the protocol utilizes animals’ tendency to frequent places where they have had rewarding experiences. The greater the reward, the stronger the draw.
The researchers fed a group of mice nicotine in their drinking water—and gave a control group plain water—for 11 days. On days 8 through 11, they injected all the mice once daily with cocaine. If the mice found the cocaine rewarding, they subsequently lingered in the cage area where they had received the injections. The nicotine-exposed mice spent 78 percent more time in that area than mice in the group that received no nicotine, even though all the mice had experienced the same number of cocaine injections. This result indicates that the mice exposed to nicotine had a greater sensitivity to cocaine’s rewarding effects. They also exhibited about twice as much cocaine-induced locomotor sensitization as mice that had not been exposed to nicotine.
The results of these behavioral tests indicate that prior chronic exposure to nicotine boosts the effects of cocaine. In other experiments, the Columbia researchers found that this priming effect only appears when cocaine administration overlaps nicotine exposure for at least 1 day. For example, in one experiment, the researchers fed a group of mice nicotine-laced water for 7 days and then waited 2 weeks before injecting the animals with cocaine. These animals reacted to the cocaine no differently than mice that had never received nicotine.
(A) Nicotine increases sensitization to cocaine’s locomotor effects: Researchers gave mice nicotine-laced or plain water for 11 days and injected some of the animals with cocaine on days 8-11 (red and green bars). All of the cocaine-injected animals exhibited locomotor sensitization: they moved about more after the fourth dose of cocaine than they did after the first. Nicotine exposure enhanced this effect (green bar).
(B) Nicotine increases conditioned place preference: Mice were given cocaine in one chamber and saline in another. When placed between the two chambers and allowed to move freely between them, the animals exhibited a marked preference for spending time in the one in which they had received cocaine. Mice that had previously been fed nicotine-laced water for 7 days (green bar) exhibited the preference in greater degree than those that had been given plain water (orange bar).
(C) Cocaine does not increase locomotor response to nicotine: Mice did not exhibit any greater increase in locomotor activity when given nicotine infusions than when infused with water. Seven days of drinking cocaine-laced water did not change this result.* P<0.05, **P<0.01
Sensitized Reward System
Examination of the animals’ brains revealed that chronic nicotine exposure amplified cocaine-induced neurobiological effects that promote addiction. Compared with the animals in the control group, nicotine-exposed animals had:
- A 74 percent increase in FosB expression in the striatum (FosB is a protein that has been shown to regulate cellular changes that underlie multiple effects of addictive drugs)
- A 40 percent greater rise in FosB mRNA levels in the striatum
- A much greater reduction in the nucleus accumbens (NAc) of long-term potentiation (LTP), the strengthening of signal transmission between nerve cells after synchronous stimulation
By increasing sensitivity to cocaine’s rewarding effects, elevations of FosB expression in the striatum enhance motivation to take the drug. LTP reductions in the NAc enhance the rewarding properties of the cocaine. The reduction in LTP is thought to compromise an inhibitory pathway, leaving the forebrain more responsive to cocaine.
The chronic-nicotine-induced increases in striatal FosB activity directly correlated with increased locomotor sensitization, conditioned place preference, and LTP attenuation. In parallel with their behavioral and neurophysiological findings, the researchers demonstrated that nicotine’s effects on FosB expression were unidirectional: Pre-exposure to chronic cocaine did not increase behavioral responses to nicotine in locomotor sensitization nor did it augment nicotine-induced attenuation of LTP.
In further experiments, the researchers traced chronic nicotine’s impact on cocaine-induced increases in FosB expression to inhibition of a group of enzymes, histone deacetylases, in the striatum. These enzymes inhibit transcription of the FosB gene (see box). When nicotine inhibits the enzymes, it weakens their inhibitory effect, and more of the FosB gene is expressed.
What About People?
The Columbia researchers next turned to a new question: Does nicotine exacerbate cocaine’s addictive effects in people as well as mice? If so, individuals who are current smokers at the time of initiating cocaine use should progress to dependence more often than individuals who are nonsmokers when they first use cocaine. With this as their hypothesis, the researchers analyzed data from the longitudinal National Epidemiological Study of Alcohol Related Consequences (NESARC). Indeed, the prevalence of cocaine dependence was 20 percent among respondents who were current smokers when they initiated cocaine use, and 6 percent among respondents who had never smoked or had stopped smoking before they first took cocaine. While not definitive, this finding suggests that smoking may increase the risk that experimenting with cocaine will lead to addiction.
Another epidemiological analysis suggested that most people who initiate cocaine use do so as current cigarette smokers, and therefore incur this increased risk. The data for the analysis were culled from detailed drug use histories provided by a cohort of 1,160 New Yorkers every month from age 15 to age 35. Sixty-five percent of the cohort had smoked at some point in their lives. Of the 28.1 percent of the cohort members who initiated cocaine use, 84.6 percent had a history of smoking and 81.2 percent of these initiated cocaine use in a month when they were actively smoking; only 18.8 percent did so in a month when they were not smoking. The finding suggests that smoking may contribute significantly to rates of cocaine dependence.
“Our results provide a powerful insight into the strong influence of a particular gateway drug. Nicotine’s effect on cocaine was dramatic and unidirectional, and we can pinpoint an epigenetic mechanism whereby nicotine amplifies cocaine’s effects,” says Dr. Eric Kandel. “Next, we plan to determine whether alcohol, a substance that is very different from nicotine but is also a gateway drug, has this same molecular effect.” As a crucial next step in this line of research, the team plans to investigate the mechanisms through which nicotine’s inhibition of histone deacetylase might influence brain receptors and neurotransmitters to boost sensitivity to cocaine.
The Columbia team’s findings point to future animal research that may further elucidate drug use patterns among people. “My epidemiological research has shown that individuals who were exposed to nicotine either prenatally or who start smoking during adolescence are more likely to smoke as adults,” says Dr. Denise Kandel. “Researchers could use available animal models to determine whether histone deacetylase inhibition—which seems to be a fundamental biological impact of nicotine—also underlies the increased risks.”
The researchers note that context and social factors are also important in the progression from using nicotine and alcohol to the abuse of illicit drugs. Just as gateway drugs may exert their influence through a biological pathway, protective factors, such as enriched environments and interactions with peers who do not use substances, also may work via neurobiology. “Scientists have developed animal models of these environmental factors and could examine whether they alter nicotine’s priming effect and inhibition of histone deacetylase,” says Dr. Denise Kandel.
“Nicotine’s inhibition of histone deacetylase might underlie the drug’s effects on organs apart from the brain and influence the health consequences of smoking,” adds Dr. Levine. For example, he notes, nicotine is associated with atherosclerosis, a condition with a negative impact on health.
“These findings were surprising,” says Dr. John Satterlee of NIDA’s Division of Basic Neuroscience and Behavioral Research. “Scientists did not expect nicotine to function as a histone deacetylase inhibitor. If validated, that finding has major public health and scientific implications. People have thought that alcohol, nicotine, and cannabis are gateway drugs because they are more accessible than other addictive substances. While that could still be true, the new findings point to a molecular mechanism, which scientists can now explore in detail.”
Epigenetic Mechanism Underlies Nicotine’s Ability to Enhance Cocaine Sensitivity
The Columbia researchers traced nicotine’s enhancement of cocaine-induced increases in FosB expression to an epigenetic mechanism. Such mechanisms regulate supplies of a protein, such as FosB, by promoting or inhibiting RNA transcription of its gene—the first step in the process of protein building. Epigenetic mechanisms may exert their effects by chemically changing DNA itself or the column of histone proteins that the DNA double helix spirals around in vine-like fashion.
Scientists have known for some time that the epigenetic effect—an increase in histone acetylation—underlies the heightened FosB expression in the striatum in response to cocaine. When acetyl groups bind to histones, these proteins and their adjacent DNA segment separate from each other. As a result, genes situated within the separated segment have increased exposure to proteins that activate their expression in the surrounding cellular environment. The rate of RNA transcription increases, and protein production rises accordingly.
Nicotine’s specific epigenetic effect, as identified by the Columbia researchers, was a reduction in the enzyme histone deacetylase in the striatum. This enzyme performs the reciprocal function to acetylation, stripping acetyl groups from histone. Normally, histone acetylation and deacetylation work in tandem, accelerating and slowing protein production in ever-changing circumstances. By inhibiting histone deacetylation, nicotine altered this balance in favor of acetylation at the site of the FosB gene, resulting in increased FosB protein production.
This study was supported by NIDA grants DA024001, DA00081, DA000081, and DA024001.
Levine, A.; Huang, Y.; Drisaldi, B.; Griffin, E.A. Jr.; Pollak, D.D.; Xu, S.; Yin, D.; Schaffran, C.; Kandel, D.B.; Kandel, E.R.. Molecular mechanism for a gateway drug: Epigenetic changes initiated by nicotine prime gene expression by cocaine, Science Translational Medicine 3(107):107ra109. Full Text