Nicotine Addiction May Have an Off Switch

Share this content:
Investigators honed in on a specific lipid transmitter, the endogenous cannabinoid 2-arachidonoylglycerol (2-AG), and found that inhibition of its enzymatic biosynthesis by diacylglycerol lipase (DAGL
Investigators honed in on a specific lipid transmitter, the endogenous cannabinoid 2-arachidonoylglycerol (2-AG), and found that inhibition of its enzymatic biosynthesis by diacylglycerol lipase (DAGL

The fact that cigarette smoking is the leading preventable cause of disease, disability, and death in the United States1 fails to be a big enough incentive for many to kick the habit for good.  It all comes down to the hold that nicotine has on the brain, but researchers from The Scripps Research Institute in La Jolla, California, may have found the “off switch.”2

In a series of experiments, the investigators honed in on a specific lipid transmitter, the endogenous cannabinoid 2-arachidonoylglycerol (2-AG), and found that inhibition of its enzymatic biosynthesis by diacylglycerol lipase (DAGL) restores the gamma aminobutyric acid (GABA) functionality compromised by chronic nicotine exposure. The study authors explained that chronic nicotine exposure alters synaptic transmission such that nicotine-induced production of 2-AG is enhanced, resulting in diminished inhibitory GABA signaling in the brain's ventral tegmental area (VTA). This leads to faulty dopaminergic signaling that may fuel the vicious cycle of nicotine craving.

The researchers used 1,2,3-triazole urea compounds to selectively inhibit 2-AG biosynthesis by DAGL in rat brains via ex vivo and in vivo techniques. To test whether inactivation of DAGLs could restore nicotine-compromised VTA GABA signaling, the researchers treated the dopamine synapses in brain slices of chronic nicotine-exposed rats with the triazole urea inhibitors KT172 and KT128 and also conducted a challenge with KT185, an inhibitor of the serine hydrase α/β-hydrolase domain 6 (ABHD6, the only significant off-target site for KT172 and KT128). Changes in nicotine-induced GABAA receptor-mediated spontaneous inhibitory postsynaptic currents (sIPSC) were then examined. Whereas KT185 had no effect on nicotine-induced sIPSCs, both KT128 and KT172 caused a return of the nicotine-evoked sIPSCs to a level akin to that seen in brain slices of nicotine-naive rats. The investigators also found that enhancing 2-AG in brain slices of nicotine-naive rats affected GABAergic function in a way similar to that seen in brain slices of chronic nicotine-exposed rats.

“When tested in rats with a history of nicotine self-administration, KT172 treatment significantly reduced voluntary nicotine intake without altering motivation for a non-drug reward, such as water self-administration by thirsty rats, or locomotor activity,”  explained lead researcher Loren H. Parsons, PhD, of The Scripps Research Institute's Committee on the Neurobiology of Addictive Disorders. “The ABHD6 inhibitory KT185 did not alter nicotine intake or any of the other evaluated behaviors,” he added. These results suggest that DAGL activity has meaningful impact on motivation for nicotine.

The findings reveal that inhibition of DAGL and 2-AG biosynthesis corrects faulty GABA signaling induced by nicotine exposure in animal models of nicotine addiction. The research provides hope for a pharmacologically mediated antidote to addiction disorders in the form of modulation of 2-AG biosynthesis. The trick is to develop therapies that prevent aberrant 2-AG activity without interfering with healthy activity of endocannabinoid receptors. The study authors also commented in a statement to the press that the development of selective pharmacologic tools for inhibiting 2-AG biosynthesis will be of substantial benefit to a broad range of studies investigating the role of endocannabinoid signaling in both normal and pathologic brain function.

“The brain endocannabinoid system participates in a number of neural processes related to reward, emotion, learning, and memory,” explained Dr Parsons, adding that endogenous cannabinoids are not synonymous with exogenous cannabinoids, such as marijuana, in the same way that endogenous opioid molecules, such as endorphins, are not the same as exogenous opioids, such as heroin.  “Long-term drug use, including tobacco smoking, can dysregulate endocannabinoid processing in a manner that motivates continued drug use and contributes to various facets of addiction.  As such, the endocannabinoid system may be a viable target for the development of therapeutics for nicotine addiction and other substance use disorders.

References

1. Centers for Disease Control and Prevention. Smoking and Tobacco Use: Fast Facts. http://www.cdc.gov/tobacco/data_statistics/fact_sheets/fast_facts/index.htm#toll. Updated April 2014. Accessed January 21, 2016.

2. Buczynski MW, Herman MA, Hsu KL, et al. Diacylglycerol lipase disinhibits VTA dopamine neurons during chronic nicotine exposure. Proc Natl Acad Sci USA. 2016; Jan 11. [Epub ahead of print]

You must be a registered member of Neurology Advisor to post a comment.

Sign Up for Free e-newsletters



CME Focus