Written by Andrew Neff

Edited by Maisha Razzaque

August 2019

Genetics of Pot Abuse

A mutant nicotine receptor provides clues about the addiction genetics

In 2019, scientists discovered an association between the prevalence of Cannabis Use Disorder and a mutant nicotine receptor in the brain (Demontis, 2019). What does it mean for diagnostics or treatment? Maybe not a ton in the near future. But what does it mean for science? 

The thing is, we kind of know how weed works. The main psychoactive ingredient is THC, which can make people feel high and is known to interact with a dedicated system of receptors in the brain. So when this study found that weed addiction was linked to a mutant nicotine receptor, it made sense that the mutation was important for brain function… but why nicotine? Why not, say, a receptor that binds THC? At first glance, it’s a mystery, but the scientists who discovered this genetic link thought they had a good idea of why.

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To understand their explanation, you first have to understand dopamine. In the first half of the 20th century, dopamine played no role in the neuroscientist's imagination. It was little more than a who-cares precursor to the much more interesting fight-or-flight molecule, noradrenaline (Marsden, 2006).

But then scientists developed a range of technologies to invasively study the living brain. Could scientists encourage certain behaviors by cranking up the dopamine? All of the experiments seemed to work: tinkering with dopamine affected the reinforcement and reward process. For example, dopamine-spiked animals would find themselves mindlessly pulling levers or preferring one room over another identical room. Today, according to many neuroscientists — whether it’s opiates, alcohol, gambling, or overeating — reinforcement and addiction are all about the dopamine (Volkow, 2017). 

In the case of THC, the authors thought, maybe the connection to dopamine is less direct. Maybe there’s a stop along the way. Perhaps, it’s the stimulation of a nicotine receptor that mediates the link. There was a study that supported this idea by showing that THC can inhibit another neurotransmitter that works on the nicotine receptor in question (Nava, 2001).

So it all comes together and the story goes: smoking weed impacts the function of nicotine receptors which impacts dopamine.

But where does the mutation come into play? How can alternative forms of this receptor make some people more susceptible to addiction? This part leads to a paradox because the mutation doesn’t actually affect the receptor itself. Instead, it affects the amount of the receptor that’s produced. People with Cannabis Use Disorder have the version of the gene that produces fewer copies. 

For those with the mutation, who therefore have fewer nicotine receptors, we might then expect a reduced impact of THC on dopamine. If that's the case, we might then expect a reduced likelihood that THC would be addictive, which is the opposite of the narrative the authors were going for. The lead author declined to comment on this apparent contradiction.

And the problems with this explanation aren’t strictly logical. Some experimental in rodents have actually shown that acute THC exposure doesn’t impact dopamine signaling at all (Castañeda, 1991). And an experiment in humans found that if THC does impact Dopamine, the effect is minimal (Bossong, 2015).

Given these issues, the explanation provided doesn’t seem to make a ton of sense. To the author’s credit, they have other ideas, for example, maybe there’s a previously underappreciated molecule in weed that’s directly interacting with the nicotine receptor. Maybe. Or maybe it’s one of the hundred other superficially plausible mechanistic links connecting weed and dopamine via a nicotine receptor. 

Maybe, more importantly, do we really need to provide a theory right away? Can’t we just accept the two are connected and wait for more research? Are the scientists who discover genetic associations the same people who should be explaining the mechanism?

With medical and recreational legalization on the horizon in much of the U.S., attitudes towards weed use are becoming much more accepting. At the same time, four million Americans are qualified for Cannabis Use Disorder, a state of intense drug dependance that few would ask for. 

The study clearly shows that people with this mutant nicotine receptor are about 30% more likely to develop an addiction to weed. It’s a finding that could perhaps argue for caution among those who are at an elevated risk. Or, a little bit more down the road, it’s possible that this study will help point us to treatments. We already block nicotine receptors to help tobacco smokers quit (although it’s a different receptor), might we be able to help weed addicts by targeting the same system?

References

  • Bossong, M. G., Mehta, M. A., van Berckel, B. N., Howes, O. D., Kahn, R. S., & Stokes, P. R. (2015). Further human evidence for striatal dopamine release induced by administration of∆ 9-tetrahydrocannabinol (THC): selectivity to limbic striatum. Psychopharmacology, 232(15), 2723-2729.

  • Castañeda, E., Moss, D. E., Oddie, S. D., & Whishaw, I. Q. (1991). THC does not affect striatal dopamine release: microdialysis in freely moving rats. Pharmacology Biochemistry and Behavior, 40(3), 587-591.

  • Demontis, D., Rajagopal, V. M., Thorgeirsson, T. E., Als, T. D., Grove, J., Leppälä, K., et al. (2019). Genome-wide association study implicates CHRNA2 in cannabis use disorder. Nature neuroscience.

  • Marsden, Charles A. "Dopamine: the rewarding years." British journal of pharmacology 147.S1 (2006): S136-S144.

  • Nava, F., Carta, G., Colombo, G., & Gessa, G. L. (2001). Effects of chronic Δ9-tetrahydrocannabinol treatment on hippocampal extracellular acetylcholine concentration and alternation performance in the T-maze. Neuropharmacology, 41(3), 392-399.

  • Volkow, N. D., Wise, R. A., & Baler, R. (2017). The dopamine motive system: implications for drug and food addiction. Nature Reviews Neuroscience, 18(12), 741.

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