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Research has shown that drugs, such as cocaine, affect the microbial composition of the gut, and that these bugs, in turn, influence how animals respond to these substances. There is, however, little understanding of how this interaction works. A mouse study published today (November 1) in Cell Host & Microbe uncovers some of the mechanisms that appear to explain the phenomenon. In it, researchers report that increased gut epinephrine levels, caused by cocaine exposure, promote the virulence of certain bacterial species. These microbes eat up the amino acid glycine, exacerbating cocaine’s effects on mice and their addiction-like behaviors.

See “Gut Microbiome Composition Linked to Human Behavior

Although previous studies “have shed data describing potential mechanisms of action altering the reward response to drugs, . . . we could say that to date there are no studies that have dissected the mechanism of action in such depth as the present study,” writes Rubén García-Cabrerizo, a neuroscientist at the APC Microbiome Ireland at University College Cork, in an email to The Scientist. García-Cabrerizo was not involved in the study.

Gut bacteria can sense the neurotransmitters of the animals in which they reside. Knowing that cocaine blocks the transporters that would ultimately enable the body to metabolize and destroy these neurotransmitters, the team tested whether exposure to the drug in mice affects the levels of neurotransmitters in the gut, and thus changes the microbiota. They infected mice with a Proteobacterial species—the murine counterpart of a pathogenic Escherichia coli in humans, Citrobacter rodentium—which, according to the team’s previous work, senses neurotransmitters from its host and increases its virulence in response to them. The team found that concentrations of the neurotransmitter norepinephrine—which is important for movement and behavior—were significantly higher in the guts of mice under cocaine treatment compared to those not exposed to it. This rise in norepinephrine indeed enhanced the ability of these microbes to invade gut cells, leading to a bloom of Proteobacteria.

Then the researchers tested how this shift in the gut microbiome affects the mice’s response to cocaine. The psychostimulant typically causes the animals to move more inside their cages, but the team expected mice infected with the pathogenic bacteria to show reduced locomotion compared to uninfected, cocaine-exposed mice because “they were so sick,” says study coauthor Vanessa Sperandio, a medical microbiologist who studies the gut-brain axis at the University of Wisconsin School of Medicine and Public Health. To their surprise, the infected mice exposed to cocaine were more active than uninfected controls exposed to cocaine.

See “Bacteria-Infecting Viruses in Gut Microbiome Linked to Cognition

Sperandio and her colleagues wondered whether this exacerbated response to cocaine stemmed from the presence of the bacteria itself or the inflammation they cause in the gut. After a series of experiments that included inducing inflammation in the absence of the microbes, they discarded the latter hypothesis. They then focused on exploring the metabolome of the animals’ guts, and found that the glycine pathway was downregulated in mice exposed to cocaine and infected with either C. rodentium or E. coli. Glycine is a neurotransmitter that has been associated with neuropsychiatric disorders, which these Proteobacteria use as a nitrogen source. Further experiments indicated that bacterial consumption had led to a drop in systemic levels of this amino acid, hinting that this shortening might be the cause of the intensified response to cocaine in infected mice, a hypothesis that the team decided to explore.

The researchers were able to reduce cocaine-induced locomotion by feeding mice with a mutant E. coli that don’t use glycine, or by supplementing the wildtype E. coli–infected animals with either glycine or a related molecule, sarcosine, which is used as a dietary supplement. The team also measured drug-seeking behavior in a setup where mice could move freely between two chambers, one of which the mice had learned to associate with cocaine ingestion. In these experiments, Proteobacteria-infected mice showed a stronger preference for the cocaine-associated chamber than those with either a normal murine microbiota or Proteobacteria that cannot use glycine.

In a recent study of their own, García-Cabrerizo and his colleagues found further evidence for the role of gut microbes in reward responses to cocaine, although unlike Sperandio, they did observe hints that inflammatory processes could be involved in this behavior. But “regardless of the similarities or differences in these studies,” he says, these works highlight “the importance of moving away from the idea that addiction is a disorder that affects only the brain.” Bringing into focus players outside the central nervous system could help in finding “interesting therapeutic targets to reverse certain addictive behaviors,” he concludes.

Sperandio says that if one could “ameliorate somebody’s addiction” by supplementing their diet with glycine or sarcosine, it would be a good alternative to toxic drugs currently aimed to treat dependence, such as lithium for opioid addiction. But she cautions that it is too early to conclude that these mechanisms apply to humans. García-Cabrerizo agrees, adding that “there is still a long way to go.”

See “Gene-Edited Skin Patch Prevents Cocaine Overdose in Mice