Julie

Flipping Molecular 'Switch' May Reduce Nicotine's Effects In The Brain

Article
Brain & Nerve
Healthy Lungs
+1
Contributed byKrish Tangella MD, MBAFeb 04, 2016

Scientists at The Scripps Research Institute (TSRI) have discovered that a lipid (fat molecule) in brain cells may act as a "switch" to increase or decrease the motivation to consume nicotine.

The team's findings in animal models point to a way that a drug might someday return this lipid to normal levels, perhaps making it easier for smokers to quit.

"We knew these lipids were implicated in nicotine addiction, but until now manipulating their synthesis was not pharmacologically feasible," said TSRI Professor Loren ("Larry") Parsons, senior author of the new study, which involved a close collaboration with the TSRI labs of Professor Marisa Roberto and Benjamin F. Cravatt, chair of the Department of Chemical Physiology and member of the Skaggs Institute for Chemical Biology at TSRI.

The study was published this week in the journal Proceedings of the National Academy of Sciences.

How Nicotine Changes the Brain

The motivation for natural rewards such as food, sex and exercise -- and also of drugs such as nicotine -- relies on neurons in the brain's reward system, based in a brain region called the ventral tegmental area (VTA). Obtaining a reward leads to excitation of these neurons and the release of a neurotransmitter called dopamine, which acts on other neurons to trigger positive emotions.

The degree to which the reward system can be activated is normally tightly controlled. A neurotransmitter called GABA (gamma aminobutyric acid) inhibits excitatory signaling in neurons and keeps the system in balance.

Chronic nicotine exposure sabotages this carefully balanced system. Previous research indicated that chronic nicotine exposure boosts the excitation of dopamine signaling while decreasing the controls on this system by GABA's inhibitory signaling. "This is thought to contribute in part to the motivation for continued nicotine use," explained Parsons.

Dopamine doesn't act alone. Nicotine exposure also leads to the release of lipids called endocannabinoids, which affect dopamine-producing neurons. Because of this, some researchers have tested potential anti-smoking therapies that block activity in the endocannabinoid receptor, where endocannabinoids bind. These treatments reduced the effects of nicotine on dopamine release and tended to reduce smoking.

"Unfortunately these treatments also produced undesirable side effects, like depression and anxiety, that limited their clinical use," said TSRI Research Associate Matthew Buczynski, who was co-first author of the study with Melissa A. Herman, senior research associate in the Roberto lab, and Ku-Lung Hsu, who was a research associate at TSRI at the time of the study and is currently an assistant professor at the University of Virginia.

The team hypothesized that instead of blocking endocannabinoid receptors throughout the brain, it would be more effective to specifically target the endocannabinoid mechanism that appears to be dysregulated by chronic nicotine.

Restoring the Brain's Balance

The new study suggests compounds called 1,2,3-triazole urea (TU) inhibitors can block the production of a specific endocannabinoid called 2-arachidonoylglycerol (2-AG).

These inhibitors were selected by Hsu for their potential to inhibit the source of 2-AG itself: an enzyme called diacylglycerol lipase. Next, Herman led studies of the cellular effects of chronic nicotine exposure on GABA signaling in rat brains. These experiments revealed a strong correlation between enhanced production of 2-AG by diacylglycerol lipase and decreased GABA levels. The team then targeted the 2-AG pathway using the 1,2,3-TU inhibitors characterized by Hsu.

"This research was a real team effort, and the quality of the science reflects the respective strengths of the team," said Herman.

The researchers found that in animal models with a history of nicotine exposure, GABA signaling returned to normal when the effects of nicotine on 2-AG production were prevented with the 1,2,3-TU inhibitors. Blocking 2-AG production also affected the motivation to consume nicotine. Buczynski observed that treating rats with the 1,2,3-TU inhibitors reduced voluntary nicotine self-administration without changing the motivation for natural rewards (for example, water self-administration by thirsty rats).

"This suggests 2-AG acts as a molecular switch for turning an important inhibitory control of dopamine neurons on and off," said Buczynski. If this switch is turned off, as in those with chronic nicotine exposure, the excitation of dopamine neurons by nicotine is less controlled, and the drug is more rewarding.

The findings could guide future therapies, perhaps enabling scientists to design therapeutics that prevent aberrant 2-AG activity without affecting other healthy activity at the endocannabinoid receptor.

The study also opens a door to new basic research, noted Parsons. Because endocannabinoids influence many aspects of behavior, inhibitors similar to 1,2,3-TU compounds may be the key to investigating normal brain function.


The above post is reprinted from materials provided by Scripps Research InstituteNote: Materials may be edited for content and length.

Disclaimer: DoveMed is not responsible for the adapted accuracy of news releases posted to DoveMed by contributing universities and institutions.

Primary Resource:

Buczynski, M. W., Herman, M. A., Hsu, K. L., Natividad, L. A., Irimia, C., Polis, I. Y., ... & Roberto, M. (2016). Diacylglycerol lipase disinhibits VTA dopamine neurons during chronic nicotine exposure. Proceedings of the National Academy of Sciences, 201522672.

Was this article helpful

On the Article

Krish Tangella MD, MBA picture
Approved by

Krish Tangella MD, MBA

Pathology, Medical Editorial Board, DoveMed Team

0 Comments

Please log in to post a comment.

Related Articles

Test Your Knowledge

Asked by users

Related Centers

Loading

Related Specialties

Loading card

Related Physicians

Related Procedures

Related Resources

Join DoveHubs

and connect with fellow professionals

Related Directories

Who we are

At DoveMed, our utmost priority is your well-being. We are an online medical resource dedicated to providing you with accurate and up-to-date information on a wide range of medical topics. But we're more than just an information hub - we genuinely care about your health journey. That's why we offer a variety of products tailored for both healthcare consumers and professionals, because we believe in empowering everyone involved in the care process.
Our mission is to create a user-friendly healthcare technology portal that helps you make better decisions about your overall health and well-being. We understand that navigating the complexities of healthcare can be overwhelming, so we strive to be a reliable and compassionate companion on your path to wellness.
As an impartial and trusted online resource, we connect healthcare seekers, physicians, and hospitals in a marketplace that promotes a higher quality, easy-to-use healthcare experience. You can trust that our content is unbiased and impartial, as it is trusted by physicians, researchers, and university professors around the globe. Importantly, we are not influenced or owned by any pharmaceutical, medical, or media companies. At DoveMed, we are a group of passionate individuals who deeply care about improving health and wellness for people everywhere. Your well-being is at the heart of everything we do.

© 2023 DoveMed. All rights reserved. It is not the intention of DoveMed to provide specific medical advice. DoveMed urges its users to consult a qualified healthcare professional for diagnosis and answers to their personal medical questions. Always call 911 (or your local emergency number) if you have a medical emergency!