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Scripps Research Institute researchers have been awarded an $8.4 million grant from the National Institute on Drug Abuse of the National Institutes of Health (NIH) to develop new compounds to help prevent relapse in smokers who are kicking the habit. Paul Kenny, a Scripps Research associate professor, is the program director and principal investigator for the study.

“This really is a broad-based, multi-disciplinary team effort,” Kenny said. “We’ve assembled a team of first-class scientists at Scripps Florida with all the experience necessary to develop novel therapeutics for the treatment of tobacco abuse.”

Others involved in the study are Michael Cameron, Theodore Kamenecka, and Patricia McDonald of The Translational Research Institute on the Scripps Florida campus.

Tobacco smoking is a global scourge, killing more than 5 million people each year worldwide, according to the World Health Organization. It is estimated that if current trends continue, by 2020 smoking will become the largest single health problem worldwide. The World Bank estimates that in high-income countries, smoking-related healthcare accounts for between 6 and 15 percent of all healthcare costs, some $160 billion annually.

Nicotine addiction is notoriously hard to break. Even with the most effective smoking-cessation agents available, more than 80 percent of smokers who quit or attempt to quit will relapse.

To combat these dismal statistics, the study is focused on an entirely new mechanism to help smokers break the habit.

That mechanism is a receptor for a specific neuropeptide (short chain of amino acids found in nerve tissue) that, when blocked, significantly decreases the desire for nicotine in animal models.

The neuropeptide, known as hypocretin-1 or orexin A, initiates a key signaling cascade that maintains tobacco addiction in human smokers. In a 2008 study in the Proceedings of the National Academy of Sciences, Kenny and colleagues showed that blocking hypocretin-1 receptors not only decreased nicotine use in animal models, but also abolished the stimulatory effects of nicotine on brain reward circuitries. These results demonstrated that hypocretin-1 plays a major role in driving the desire for more nicotine.

These findings also highlighted the importance of hypocretin-1 receptors in a region of the brain called the insula, a walnut size part of the frontal lobe. While all mammals have insula regions that sense the body’s internal physiological state and direct responses to maintain homeostasis, this region has also been implicated in cravings. In one study, it was reported that smokers who sustained damage to the insula lost the desire to smoke, an insight that revealed the insula as key for sustaining the tobacco habit in smokers.

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