Compound found in gut could help reduce cocaine addiction

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US scientists believe they may be on to a possible cure for cocaine addiction with the help of bile acids, the gut compounds used for digestion, writes Colm Gorey for Silicon Republic.

When it comes to solving a major health problem such as cocaine addiction, scientists from Vanderbilt University Medical Center believe an answer could lie in our own body.

In a paper published to PLOS Biology, a research team at the university found strong evidence that bile acids – gut compounds used by the digestive system to break down dietary fats – could reduce the desire for cocaine.

Those in the team have long studied metabolic changes associated with bariatric surgery for weight loss, with patients typically experiencing dramatic changes in glucose regulation and taste preferences when in recovery.

Realising that something beyond our understanding was happening, the researchers questioned whether elevated serum bile acids – a common effect of bariatric surgery – were affecting the reward centres of the brain for fatty foods.

In the most common type of bariatric surgery, Roux-en-Y gastric bypass, the surgeon restricts the size of the stomach and alters the path of the food through the digestive tract. This also changes where bile acids enter the small intestine, increasing the circulation of the acids in the body.

The results

Testing this theory in mice using a procedure called bile diversion, the researchers connected the gall bladder of a mouse to its small intestine.

For obese mice, the procedure reduced their weight and desire for fatty foods; in normal-weight mice, the procedure reduced cocaine-induced increases in brain dopamine release and also reduced cocaine-associated behaviours.

Expanding on this knowledge, a synthetic bile acid drug called obeticholic acid (OCA) was given to mice without surgery.

Once again, it was shown to reduce a desire for cocaine and that the bile acid receptor TGR5 mediates the effects of elevated bile acids in the reward circuitry of the brain.

“Will bile acids cure cocaine addiction in humans? We don’t know, but our research certainly suggests that bariatric surgery or consumption of bile acids may have beneficial effects,” said Charles Flynn of the research team.

“OCA is already clinically approved, so it might be possible to move quickly to clinical trials of its efficacy in treating addiction.”

Bile diversion, a bariatric surgery, and bile acid signaling reduce central cocaine reward

The gut-to-brain axis exhibits significant control over motivated behavior. However, mechanisms supporting this communication are poorly understood. We reveal that a gut-based bariatric surgery chronically elevates systemic bile acids and attenuates cocaine-induced elevations in accumbal dopamine. Notably, this surgery reduces reward-related behavior and psychomotor sensitization to cocaine.

Utilizing a knockout mouse model, we have determined that a main mediator of these post-operative effects is the Takeda G protein-coupled bile acid receptor (TGR5). Viral restoration of TGR5 in the nucleus accumbens of TGR5 knockout animals is sufficient to restore cocaine reward, centrally localizing this TGR5-mediated modulation.

These findings define TGR5 and bile acid signaling as pharmacological targets for the treatment of cocaine abuse and reveal a novel mechanism of gut-to-brain communication.

Author summary

Communication between the gut and the brain is increasingly being appreciated as influencing motivated behavior. The gut can influence brain function through secreted hormones traveling through the blood and entering the brain. We utilize a weight-loss surgery designed to elevate one class of circulating hormones, bile acids, to show their action in the brain and their role in modulating behaviors associated with the addictive properties of cocaine. This surgery reduces the reward-related behavior and the psychomotor effects of cocaine.

Furthermore, we utilize a knockout mouse model to reveal that a specific bile acid receptor mediates some of the effects of bile acids over motivated behavior.

Viral intervention studies localize this effect to a receptor population within the nucleus accumbens, a brain region central to the processing of reward. These findings identify a role for bile acids in blunting cocaine’s ability to alter brain function, generating novel and exciting directions for the treatment of cocaine abuse.

Authors

India A. Reddy, Nicholas K. Smith, Kevin Erreger, Dipanwita Ghose, Christine Saunders, Daniel J. Foster, Brandon Turner, Amanda Poe, Vance L. Albaugh, Owen McGuinness, Troy A. Hackett, Brad A. Grueter, Naji N. Abumrad, Charles Robb Flynn and Aurelio Galli.

Report on the Silicon Republic site Article on the Plos Biology site

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