Scientists discover that blocking a neuropeptide receptor decreases nicotine addiction



University of Rochester Medical Center scientists discovered a gene mutation that impairs the placenta and also is influential in cancer development, according to a study published online December 16, 2008, in the journal PLoS (Public Library of Science) Biology. The investigation is the first to link the key placental gene, SENP2, to the well-known p53

Full Post: Study of placenta unexpectedly leads to cancer gene

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.

In addition, the study highlighted the importance of hypocretin-1 receptors in a brain region called the insula, a walnut size part of the frontal lobe of the brain. A highly conserved brain region, all mammals have insula regions that sense the body’s internal physiological state and direct responses to maintain homeostasis. The insula has also been implicated in regulating feelings of craving. In a recent groundbreaking study, it was reported that smokers who sustained damage to the insula lost the desire to smoke, an insight that revealed the insula as a key brain region that sustains the tobacco habit in smokers. Until the new study, however, the neurobiological mechanisms through which the insula regulated the persistence of tobacco addiction remained unclear.

The new study sheds light on this question, showing that hypocretin-containing fibers project significantly to the insula, that hypocretin-1 receptors are expressed on the surface of neurons in the insula, and that blockade of hypocretin-1 receptors in the insula, but not in the adjacent somatosensory cortex region (which also records and relays sensory information), decreases nicotine self-administration. The effects of blocking hypecretin-1 receptors only in the insula, however, were less than blocking these receptors in the brain as a whole, suggesting that hypocretin transmission in other brain regions may also be playing a role in nicotine reward.

Working with scientists from Scripps Florida’s Translational Research Institute, Kenny and his colleagues are now searching for new antagonists at hypocretin-1 receptors that are less toxic than the compound used in the published experiments in the hopes of furthering the development of a human therapy.

http://www.scripps.edu/

Link




Scientists have identified a relationship between two proteins in the brain that has links to both nicotine addiction and autism. The finding has led to speculation that existing drugs used to curb nicotine addiction might serve as the basis for potential therapies to alleviate the symptoms of autism. The discovery identified a defining role for

Full Post: A link found between nicotine addiction and autism



A new study from the Abramson Cancer Center and Department of Psychiatry in the University of Pennsylvania School of Medicine shows that smokers who carry a particular version of a gene for an enzyme that regulates dopamine in the brain may suffer from concentration problems and other cognitive deficits when abstaining from nicotine - a problem

Full Post: Researchers find inherited genetic variation in nicotine addiction



Just seeing someone smoke can trigger smokers to abandon their nascent efforts to kick the habit, according to new research conducted at Duke University Medical Center. Brain scans taken during normal smoking activity and 24 hours after quitting show there is a marked increase in a particular kind of brain activity when quitters see photographs

Full Post: Why stopping smoking is hard



Tobacco use is more prevalent and smoking cessation less likely among persons with Attention Deficit Hyperactivity Disorder (ADHD). In a study of smokers with attention deficit and hyperactivity symptoms, those who exhibited elevated hyperactivity and impulsivity, with or without inattention, showed lower quit rates after 8 weeks than those with inattention symptoms alone or those

Full Post: Researchers study effect of ADHD on smoking cessation



Nicotine gum has been in use for over 20 years to help smokers quit abruptly yet close to two-thirds of smokers report that they would prefer to quit gradually. Researchers from the University of Pittsburgh and GlaxoSmithKline Consumer Healthcare have now found that smokers who are trying to quit gradually can also be helped by

Full Post: Nicotine gum effective for gradual smoking reduction and cessation