The study was published in an online Early Edition issue of the Proceedings of the National Academy of Sciences, the week of November 24.
Scripps Florida is a division of The Scripps Research Institute.
The neuropeptide, hypocretin-1 (Orexin A), may initiate a key signaling cascade, a series of closely linked biochemical reactions, which maintains tobacco addiction in human smokers and could be a potential target for developing new smoking cessation treatments.
"Blocking hypocretin-1 receptors not only decreased the motivation to continue nicotine use in rats, it also abolished the stimulatory effects of nicotine on their brain reward circuitries," said Paul Kenny, Ph.D., the Scripps Research scientist at Scripps Florida who led the study. "This suggests that hypocretin-1 may play a major role in driving tobacco use in smokers to want more nicotine. If we can find a way to effectively block this receptor, it could mean a novel way to help break people's addiction to tobacco."
Cigarette smoking is one of the largest preventable causes of death and disease in developed countries, and accounts for approximately 440,000 deaths and $160 billion in health-related costs annually in the United States alone. Despite years of health warnings concerning the well-known adverse consequences of tobacco smoking, only about ten percent of smokers who attempt to quit annually manage to remain smoke free after one year, highlighting the difficulty in quitting the smoking habit.
In the study, Kenny and a postdoctoral fellow in his laboratory, Jonathan Hollander, Ph.D., blocked the hypocretin-1 receptor using low doses of the selective antagonist SB-334867, a commercially available compound often used in research.
"While hypocretin 2 systems, otherwise known as orexin B, have been mainly implicated in regulating sleep," Kenny said, "hypocretin 1, also known as orexin A, appears to be more involved in regulating motivated behavior. Our previous studies in close collaboration with other Scripps Research scientists have shown that hypocretin-1 receptors play a central role in regulating relapse to cocaine seeking. With that in mind, it seemed reasonable to test whether it was involved in nicotine reward as well."
The new study indeed showed that blocking the receptor in rats significantly decreased nicotine self-administration and also the motivation to seek and obtain the drug. These findings suggest that hypocretin-1 receptors play a critical role maintaining nicotine-taking behavior in rats, and perhaps also in sustaining the tobacco habit in human smokers.