Mice on drugs

A tiny genetic change could alter the way the brain craves THC

One genetic variant may predispose mice — and people — towards a THC craving.

Plenty of people experiment with weed, but only some will ever become truly dependent on it. Between 30 percent and 10 percent of people struggle with marijuana use disorder, depending on who you ask, and scientists are still trying to figure out why some people struggle to quit more so than others. A new study provides at least one "contributing factor" that begins in a single gene and affects the brain during teen years.

In a mouse study, a team of scientists at Cornell University found evidence that one genetic variant may predispose mice towards a THC craving – especially if it's found in female teenage mice. They discovered that this genetic variant, called the FAAH polymorphism, is related to "hyperconnectivity" between two areas of the brain's reward system.

This hyper-connectivity, the study suggests, was linked to a greater preference for THC – a pattern that persisted even once those mice reached adulthood.

Although this was a study done in mice, genetic research has shown that these genetic mutations exist in humans too. About 38 percent of people of European descent carry the variant that these scientists propose could affect THC preferences, the study notes.

Based on her earlier work in humans and mice with this gene, Caitlin Burgdorf — the study's first author —tells Inverse that she believes there may be more carryover to humans than you might expect from a mouse study.

"As a result, we predict that our current behavioral and anatomical findings of the role of the FAAH polymorphism in addiction-related phenotypes will translate to humans," she says.

The study was published Wednesday in Science Advances.

Exposure to marijuana during teenage years an influence later use, and a genetic variant could speed that process along, this study suggests.

Why FAAH polymorphism matters

Ultimately, this genetic variant messes with the activity of an enzyme in the brain called fatty acid amide hydrolase (FAAH), which affects the body's endocannabinoid system.

The endocannabinoid system is a series of neurotransmitters and receptors throughout the body that regulate mood, the experience of pain, and numerous other experiences. The body naturally produces endocannabinoids (they're responsible for the runner's high, for example). But marijuana is also a potent source of them, but in the case of the drug, they're called exogenous cannabinoids since they come from an outside source.

The mechanism these scientists wanted to test affects one of those main endocannabinoid receptors called CB-1. When FAAH is functioning naturally, it regulates an endocannabinoid that binds to that receptor. As the authors note in the paper, the functionality of FAAH has "widespread" effects on the way people behave around drugs.

For instance, a 2019 trial published in The Lancet Psychiatry found that a drug that can impair FAAH can help wean people off of marijuana. Other studies, conducted on humans, have found that people with the same genetic change seen in these mice were more likely to be dependent on marijuana compared to those who had a different genotype.

"Human studies showed that the FAAH polymorphism is associated with problem drug use and an increased likelihood to try cannabis in the first place," says Burgdorf. "Our study showed the mechanism by which this may be happening."

Here, the scientists wanted to see how FAAH activity impacted THC preferences in mice, by digging deep into their reward systems. Ultimately, they found that in the mice who lacked FAAH activity due to their genes had greater connectivity between the ventral tegmental area (VTA) and the nucleus accumbens. This is a crucial pathway through which dopamine (the neurotransmitter related to reward) is shuttled through the brain.

This "hyperconnectivity," as the scientists put it, played out in how the mice approached THC.

If you give a mouse some THC

In the experiment, the team put mice with the genetic variant and those without it into a two-roomed cage. In one room, they were given a THC solution and learned to associate that room with the drug. In the other, the mice stayed sober.

The mice without the polymorphism didn't seem to enjoy their high very much, and they steered clear of the THC room. But the mice with the polymorphism preferred the room where they got the THC. Importantly, that pattern seemed to stick with the mice even as they reached adulthood.

The mice without the polymorphism didn't seem to enjoy their high very much.Shutterstock

In a statement, the authors suggested that one day this variant could help predict whether someone (a teen girl, going by this study) may struggle with marijuana dependency. However, this one study on one gene isn't enough to truly capture that risk.

There are plenty of reasons that people may turn to marijuana in the first place and stick with it, ranging from their own anxiety to sleeplessness to social pressures.

But what this study can do is show how marijuana may have unique effects on the brains of different people, and that those effects are moderated by things from our brain's reward systems, to our genes.

The teenage brain is an already tumultuous place that changes rapidly, and for some, this variant may change that way marijuana interacts with that complicated environment. These effects may last a lifetime.

Abstract: Adolescence represents a developmental period with the highest risk for initiating cannabis use. Little is known about whether genetic variation in the endocannabinoid system alters mesolimbic reward circuitry to produce vulnerability to the rewarding properties of the exogenous cannabinoid -tetrahydrocannabinol (THC). Using a genetic knock-in mouse model (FAAHC/A) that biologically recapitulates the human polymorphism associated with problematic drug use, we find that in adolescent female mice, but not male mice, this FAAH polymorphism enhances the mesolimbic dopamine circuitry projecting from the ventral tegmental area (VTA) to the nucleus accumbens (NAc) and alters cannabinoid receptor 1 (CB1R) levels at inhibitory and excitatory terminals in the VTA. These developmental changes collectively increase vulnerability of adolescent female FAAHC/A mice to THC preference that persists into adulthood. Together, these findings suggest that this endocannabinoid genetic variant is a contributing factor for increased susceptibility to cannabis dependence in adolescent females.

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