Earlier studies have indicated cocaine can alter the composition of gut microbiota and conversely, a depleted gut microbiota affects how one responds to cocaine. However, molecular mechanisms underlying such bidirectional interactions are unclear.

A study published on November 1st in the journal Cell Host & Microbe clarifies key molecular steps in the complex crosstalk among exposure to cocaine, microbial metabolism, and neuronal function in the brain. The collaborative study includes scientists from the University of Wisconsin School of Medicine and Public Health, the University of Texas Southwestern Medical Center, IBR-CONICET-UNR and PLABEM in Argentina, and the University of Quebec at Montreal.

Exposing mice to cocaine, the researchers observed an increase in the neurotransmitter norepinephrine in the gut, which preferentially promoted the colonization of the gut by a class of bacteria called gamma-proteobacteria, which include E. coli. The expanded population of gamma-proteobacteria in the gut consumed glycine, depleting the amino acid in the host’s gut, blood and cerebrospinal fluid. Glycine is vital for normal brain function. Through a ramification of functional consequences, the depletion of glycine heightened addiction-like behavior in the mouse model, such as cocaine-induced increase in locomotion and exploration.

By supplementing cocaine-exposed mice with glycine, the investigators noted the heightened addiction-like behaviors recede to normal levels. A similar reduction of excessive locomotion and exploration is also seen when mutant gamma-proteobacteria that cannot consume glycine are transplanted into cocaine-exposed mice, preventing the depletion of glycine in the host.  These observations indicate glycine mediates addiction-like behavior in mice exposed to cocaine.

The investigators found cocaine in the gut of mice activates a receptor protein (QseC) that promotes the growth of gamma-proteobacteria that outcompete resident gut flora.

“The gut bacteria are consuming all of the glycine and the levels are decreasing systemically and in the brain,” said Vanessa Sperandio, PhD, a professor of medical microbiology & immunology at the University of Wisconsin School of Medicine and Public Health and the senior author of the study. “It seems changing glycine overall is impacting the glutamatergic synapses that make the animals more prone to develop addiction.”

Using metabolomic analyses, the authors show altered levels of glycine play a role in cocaine-induced transcriptional plasticity in the mouse nucleus accumbens, a region of the brain dubbed the pleasure center.

“Usually, for neuroscience behaviors, people are not thinking about controlling the microbiota, and microbiota studies usually don’t measure behaviors, but here we show they’re connected” said Santiago Cuesta, PhD, a postdoctoral researcher at the University of Wisconsin School of Medicine and Public Health and the lead author of the study. “Our microbiome can actually modulate psychiatric or brain-related behaviors.”

The authors claim the mechanisms reported in the current study could be used to modulate reward-related brain circuits that contribute to substance use disorders. Sperandio believes inter-disciplinary teams bridging microbiology and neuroscience will help identify causes of different neuropsychiatric disorders instead of simply establishing correlation.

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