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TSRI Scientists Find that Nicotine Use Increases Compulsive Alcohol Consumption

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Why do smokers have a five to ten times greater risk of developing alcohol dependence than nonsmokers? Do smokers have a greater tendency toward addiction in general or does nicotine somehow reinforce alcohol consumption?

Now, a study led by scientists at The Scripps Research Institute (TSRI) helps provide insight into these questions, showing that, in rat models, nicotine exposure actually promotes alcohol dependence.

“It’s a vicious cycle,” said TSRI biologist Olivier George, a senior author of the new study. “Nicotine makes individuals crave alcohol to ‘reward’ the brain and reduce stress.”

In the study, published April 14, 2015, in The Journal of Neuroscience, the researchers also showed that the combination of nicotine and alcohol activated a unique group of neurons, giving positive reinforcement to continue alcohol and nicotine use.

In conducting the new research, the team first tested whether nicotine exposure could affect alcohol-drinking behavior in rat models. They started with two groups of male rats. Both groups were given access to alcohol to establish the baseline of how much they would drink. The rats drank a little bit, perhaps the equivalent of one or two beers for a human, but they stopped before showing signs of drunkenness.

After this baseline test, the researchers used alcohol vapor to induce alcohol dependence in one group of rats. Dependence developed in about two months. In subsequent tests where alcohol was freely available, these rats consumed the equivalent of a six-pack of beer and had blood alcohol levels close to three times the legal limit for humans.

The second group of rats was exposed to both nicotine and alcohol vapor. These rats developed alcohol dependence much faster—and they began drinking the equivalent of a six-pack in just three weeks. “We had never seen such a rapid escalation of alcohol drinking before,” said George.

The researchers then offered the rats alcohol with the bitter compound quinine added to see if they could stop the rats from drinking. Most rats decreased their alcohol consumption to avoid the bitter taste, but the nicotine-exposed rats just kept drinking. This indicated that their behavior was compulsive, much like alcoholism in humans.

Using further neurological studies, George and his colleagues tracked this compulsive behavior to the activation of “stress” and “reward” pathways in the brain.

Previous studies from George’s lab had shown that nicotine activates certain “reward” neurons in the brain—giving positive reinforcement to keep smoking. At the same time, nicotine activates “stress” neurons in the brain, giving negative reinforcement. This stress can lead individuals to crave alcohol to both activate the reward system and calm the stress system.

The compulsive alcohol consumption and neurological pathways seen in the new study suggest that alcohol works with nicotine to further activate the brain’s reward system and dampen the stress of nicotine exposure.

This interaction may explain why it is difficult for smokers to quit drinking, and vice versa. Interestingly, the combination of neurons activated by nicotine and alcohol together is different from the neurons activated by each substance on its own.

“Now we can try to find compounds that will specifically inactivate those neurons,” said George.

In addition to George, other authors of the paper, “Chronic Nicotine Activates Stress/Reward-Related Brain Regions and Facilitates the Transition to Compulsive Alcohol Drinking,” were Fabio C. Cruz and Bruce T. Hope of the Behavioral Neurosciences Branch of Intramural Research Program of the National Institute on Drug Abuse, part of the National Institutes of Health (NIH), a component of the U.S. Department of Health and Human Services (IRP/NIDA/NIH/DHHS); Leandro F. Vendruscolo, Giordano de Guglielmo and Marian L. Logrip of TSRI; George Koob of TSRI; and Rodrigo M. Leao of IRP/NIDA/NIH/DHHS, TSRI and the University of Estadual Paulista.

Scientists Detail Critical Role of Gene in Many Lung Cancer Cases.

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Scientists from the Florida campus of The Scripps Research Institute (TSRI) have shown that a well-known cancer-causing gene implicated in a number of malignancies plays a far more critical role in non-small cell lung cancer, the most common form of the disease, than previously thought.

These findings establish the gene as a critical regulator of lung cancer tumor growth. This new information could turn out to be vital for the design of potentially new therapeutic strategies for a group of patients who represent almost half of non-small cell lung cancer cases.

In the study, published online ahead of print by the journal Cancer Research, the scientists found that presence of known oncogene Notch 1 is required for survival of cancer cells. In both cell and animal model studies, disabling Notch 1 leads to a rise in cancer cell death.

“While Notch signaling has emerged as an important target in many types of cancer, current methodologies that target that pathway affect all members of the Notch family, and this has been associated with toxicity,” said Joseph Kissil, a TSRI associate professor who led the study. “We were able to identify Notch 1 as the critical oncogene to target, at least in a common form of lung cancer.”

The new findings show that Notch1 is required for initial tumor growth, as it represses p53, a well-known tumor suppressor protein that has been called the genome’s guardian because of its role in preventing mutations. The p53 protein can repair damaged cells or force them to die through apoptosis — programmed cell death.

Using animal models, the study shows that inhibition of Notch1 signaling results in a dramatic decrease in initial tumor growth. Moreover, disruption of Notch 1 induces apoptosis by increasing p53 stability — substantially increasing its biological half-life, for example.

These findings provide important clinical insights into the correlation between Notch1 activity and the poor prognosis of non-small cell lung cancer patients who carry the non-mutated form of the p53 gene. “If you look at lung cancer patient populations, Notch signaling alone isn’t a prognostic indicator, but if you look at p53-positive patients it is,” Kissil said.

Source: http://www.sciencedaily.com