Hidden body signal may help explain compulsive drug use

The search for cocaine addiction genes led somewhere no one expected: the liver, not the brain.

 Rats in a self-administration study press a lever for cocaine at whatever pace their biology allows.  Watch the timing closely, and the gaps between hits reveal how compulsive that drug use becomes.

 A team studying nearly 900 of these animals went looking for the genes behind that timing.  What they found sat nowhere near the brain.

 Clue hidden in metabolism

 To the liver, the trail led. The scientists who discovered the signal didn't look for it. They were busy mapping genetics across hundreds of animals when it surfaced.

 The project came out of the University of California, San Diego (UC San Diego), where Olivier George, Ph.D., helped lead the behavioral work.  His lab let nearly 900 rats decide how much cocaine to take.https://www.effectivecpmnetwork.com/gr1hdw2ws?key=0b7c754200d6c5cdacfb68d29605121a

 The evidence presented a new perspective on addiction. The clearest genetic signal sat over a cluster of genes that build an enzyme the body uses to break cocaine apart.  Not a brain gene at all.

 Cocaine addiction genes

 When each animal is nearly identical, it is difficult to attribute a behavior to a single gene. Cocaine trouble runs in families, as one review of human genetics makes clear, yet the exact genes have stayed hidden.

 So the team used rats bred to carry the genetic variety seen across people.  Building that population took years.

 The majority of the animals were obtained through a breeding program at Wake Forest University School of Medicine over the course of roughly eight years and twenty distinct cohorts. The rats sorted themselves out with a lever and a constant supply. Some barely touched the drug.  Others escalated hard, a few pressing for more than 150 hits in a single six-hour session.

 That same gulf between heavy and light users runs through human populations, which is exactly why the mixed genetics paid off.

 What the enzyme does

 The enzyme belongs to a family called carboxylesterase, produced largely in the liver.  One of its main jobs is breaking cocaine into pieces that the body can shrug off.

 How quickly it works helps set how long a dose lasts and how hard it hits.  In the rats, tiny variations in two of these genes tracked a single behavior: the gap each animal left between hits.

 Rats that waited less between doses tended to take far more cocaine overall.  Less pause, more drug.

 What those variations actually do to the enzyme is still unknown.  The team did not measure cocaine breakdown directly, so whether the changes speed it up or slow it down remains an open question.

 Signal seen in humans

 Rats are not people, and as a result, one does not always hold in the other.  So one finding stood out.  In genetic studies of cocaine addicts, a gene known as Trak2 had already been identified. This overlap is useful and uncommon. Human genetics has been slow to give firm answers about cocaine, as one recent paper on self-control makes clear.  The same gene in rats bridges the two species.

 The carboxylesterase signal was the fresh one.  No earlier work had tied this style of cocaine use in rats to the genes that break the drug down.

 A few of the other genes they flagged have surfaced before in research on drinking and smoking.

 Body and brain together

 None of this erases the brain.  Several other genes in the study point to reward and stress circuits, including the dopamine pathways, cocaine floods to produce the rush users chase.

 Addiction research has centered on the brain for decades, and these results suggest the body’s own chemistry deserves a seat at the table.

 “It reminds us that addiction isn’t only in the brain.  It’s a complex puzzle involving how the entire body processes the drug,” said George.

 There is also a larger theme at play here. Many genes tied to one drug turn out to influence others.  That pattern has been traced in individuals by a recent study that looked at several substance use disorders. Cocaine, though, leans on its own breakdown chemistry in a way that looks specific.

 New treatment target

 Here is what the work makes newly clear.  Genes controlling how the body breaks cocaine down are linked to how compulsively rats keep using it.  No study this large had made that connection before.

 A treatment target that is not the brain appears to be real for the first time. If a medicine could change how fast the body clears cocaine, it could dull the drug’s grip without rewiring the brain’s reward system.

 First author Montana Kay Lara, a postdoctoral researcher at UC San Diego, sees a concrete test ahead.

 Lara stated, "It gives us a concrete target to test whether changing the metabolization of cocaine can blunt the drive toward compulsive use." The next step is to determine whether nudges can lessen the pull in living animals and how those gene changes affect the enzyme. The team also banks blood, brain, and other tissues from these animals.  They hope it can reveal early markers of who is most at risk.

 A drug that works on the body rather than the mind would be a real departure for addiction medicine.

 The study is published in the journal Nature Communications.

  Writer: Binod Kumar Simkhada 

binodkumarsimkhada315@gmail.com