Can Scientists Turn Off "Switch" To Nicotine Cravings?

By Victoria Kim 01/15/16

Researchers at Scripps may have opened the door to future medications to help people quit smoking.


A research team at The Scripps Research Institute was able to shut off a “switch” in the brain that affects the desire to consume nicotine. Based on the animal model used in the study, the team’s findings could guide future therapies for smoking cessation.

The “switch” is actually a lipid, or fat molecule, in brain cells that can increase or decrease the motivation to consume nicotine. "We knew these lipids were implicated in nicotine addiction, but until now manipulating their synthesis was not pharmacologically feasible,” said Professor Loren Parsons from The Scripps Research Institute (TSRI).

Past studies on anti-smoking treatments have typically focused on blocking activity in the endocannabinoid receptor, where endocannabinoids bind. These treatments were able to produce the desired effect, to reduce the effects of nicotine and dopamine release and to reduce smoking, but the effects were not 100% positive.

“Unfortunately these treatments also produced undesirable side effects, like depression and anxiety, that limited their clinical use,” said TSRI Research Associate Matthew Buczynski.

Endocannabinoids are known to play a role in numerous physiological processes including appetite, memory, and pain.

For this study, which was published in the journal Proceedings of the National Academy of Sciences, the research team decided to try targeting the specific endocannabinoid mechanism (2-arachidonoylglycerol, or 2-AG) rather than blocking endocannabinoid receptors throughout the brain.

Using 1,2,3-TU inhibitors to block production of the 2-AG endocannabinoid reduced the rats’ desire to consume nicotine without changing their motivation for natural rewards (e.g. thirsty rats drinking water).

This suggests that the 2-AG endocannabinoid “acts as a molecular switch for turning an important inhibitory control of dopamine neurons on and off,” said Buczynski.

When the 2-AG switch is turned off, i.e., when its production is blocked, the excitation of dopamine neurons by nicotine is less controlled and the drug is more rewarding.

This is similar to the effect of chronic nicotine exposure, which disrupts a carefully balanced system by boosting the excitation of dopamine signaling while decreasing GABA (gamma aminobutyric acid) signaling, which keeps the system in balance by inhibiting excitatory signaling. This imbalance “is thought to contribute in part to the motivation for continued nicotine use,” said Parsons.

The researchers found that in animal models with a history of nicotine exposure, signaling was restored to normal when the effects of nicotine on 2-AG endocannabinoid production was prevented by the 1,2,3-TU inhibitors.

This research could guide future smoking cessation therapies and enable scientists to design treatments without affecting other healthy activity.

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