Researchers Show How VNS May Enhance Drug Addiction Treatment

A research team from The University of Texas at Dallas has demonstrated in a preclinical study that vagus nerve stimulation (VNS) might assist in retraining the brain at the cellular level to decrease drug-seeking behavior via a specific neuromodulator.

Dr. Sven Kroener, associate professor of neuroscience in the School of Behavioral and Brain Sciences, is corresponding author of the study, published in the June 5 issue of The Journal of Neuroscience. His team focused on the role of brain-derived neurotrophic factor (BDNF), a common nerve growth factor that regulates synaptic transmission and that is released in the brain in response to VNS.

Previous research in rodents has shown that BDNF, when infused into the brain in the prefrontal cortex, which regulates emotions and actions, reduces drug-seeking behavior. Other studies have shown that VNS enhances BDNF release.

"If VNS can reverse the brain changes caused by drugs, that would give us a starting point to understand the therapeutic potential of VNS to treat substance-use disorders."

cognition and neuroscience doctoral student Christopher Driskill

"We merged these two ideas," Kroener said. "If BDNF by itself reduces drug-seeking, can we reduce drug-seeking through VNS?"

Drug and alcohol abuse can alter the brain in ways that impair control over drug-seeking impulses, Kroener said. Extinction learning is a therapeutic approach that creates new alternative behaviors that compete with existing habits. The therapy breaks the relationship between an established stimulus and response.

"Addiction makes fundamental chemical changes in the brain. Extinction training works to restore previous conditions and is one of the most effective ways to treat drug addiction," Kroener said. "When accompanying extinction training, VNS could accelerate these restorations. We are trying to pin down what VNS-aided extinction training is doing at the chemical and cellular levels."

Cognition and neuroscience doctoral student Christopher Driskill, lead author of the paper, said that deficits in BDNF signaling are known to arise from drug use.

"Drugs such as cocaine reduce the response to BDNF, making it a promising target for therapeutics," he said. "If VNS can reverse the brain changes caused by drugs, that would give us a starting point to understand the therapeutic potential of VNS to treat substance-use disorders."

In VNS, electrical pulses are sent to the brain through the vagus nerve via a device implanted in the neck. Pioneering work by UT Dallas researchers has demonstrated that stimulating the nerve during physical rehabilitation can rewire areas of the brain damaged by stroke, leading to improved recovery. The technique also has been approved by the Food and Drug Administration for treating epilepsy and major depression.

"The field is growing very rapidly, as are the applications, but the science behind it is still in its infancy," Kroener said. "We're coming from the cellular side, from the systems neuroscience side, trying to understand how this works."

In the current study, rats trained in drug-seeking behavior received 10 days of VNS-enhanced extinction training. BDNF levels in their brains were elevated after just a single VNS extinction session, and they exhibited reduced drug-seeking behavior.

Because VNS can induce the release of several neurotransmitters, the researchers then blocked a primary receptor for BDNF called tropomyosin receptor kinase B (TrkB) during extinction training.

"VNS reverses drug-induced changes in the infralimbic cortex of the medial prefrontal cortex," Kroener said. "But the effect was blocked by the TrkB antagonist; animals receiving the blocker did not benefit from VNS. This strongly suggests that BDNF is indeed required to reduce drug-seeking through VNS."

Another experiment in the study indicated that VNS also seems to increase the staying power of the restorative changes to the brain. Excessive drug use alters not only individual brain cells, but also the network connections between them, Kroener said.

"We found that the conditions in the brain change back to how they were when drug-seeking behavior was high - but only in the animals that did not receive VNS," he said. "So, VNS might protect the network changes occurring due to extinction learning. If so, BDNF is required for that protection as well."

Kroener said that while the therapeutic effects of VNS have been documented for a few medical conditions, more research is needed to understand better how it works and how to refine the technique for improved outcomes, including, potentially, for addiction.

"It's always important to understand the mechanisms through which a therapy works. Only then can you potentially improve the treatment," he said.

Additional authors of the paper associated with UT Dallas include cognition and neuroscience doctoral student Sierra R. Rodriguez and five alums: Jessica E. Childs BS'12, MS'14, PhD'18, a postdoctoral researcher at the University of California, Irvine; Aarron Phensy BS'14, PhD'20, a postdoctoral researcher at UC San Francisco; John T. O'Brien MS'22, an MD/PhD student at UT Medical Branch in Galveston; Kathy Lindquist MS'20, a neuroscience doctoral student at the Medical University of South Carolina (MUSC); and Aurian Naderi BS'21, a doctoral student at Rice University. Other contributing authors are Dr. Jacqueline McGinty and Bogdan Bordieanu at MUSC.

The research was funded by a grant from the National Institute on Drug Abuse, a component of the National Institutes of Health.