Relapse is a common feature of recovery from substance abuse – two out of three patients treated for substance abuse disorder in the United States relapse within 12 months, according to the Journal of the American Medical Association.
Substances of abuse hijack the brain’s pleasure and reward systems, reinforcing drug-seeking behaviors by flooding the system with “feel-good” chemicals, while producing long-lasting functional changes in areas of the brain. regulate decisions and motivation.
Combined, these hard-wired biological changes make drug cravings harder for some to ignore, but researchers are developing new ways to prevent relapses by chemically altering individual components of neural networks, leaving the rest of the brain untouched.
In new findings published in Neuron, neuroscientists at the University of California at San Diego and VTC’s Fralin Biomedical Research Institute have identified the specific brain circuit that triggers cocaine relapse in mice. When they applied a molecular brake to block activity in this circuit, the mice completely lost their previously hungry interest in the drug, resuming normal behavior.
They went back to baseline – as if they had never been exposed to the drug before. We have discovered a hidden molecular regulator that may play a key role in understanding the tendency to relapse. “
Byungkook Lim, associate professor of biological sciences at UC San Diego and lead author of the study
Lim said the discovery builds on previous research into how substances of abuse – cocaine, alcohol, tobacco and other illicit drugs – alter dopamine signaling pathways in the brain, contributing to addiction, a chronic disease that affects 10 percent of American adults, according to the National Institute on Alcohol Abuse and Alcoholism.
The research team, which included co-author Sora Shin, who is now an assistant professor at the Fralin Biomedical Research Institute and the Department of Human Nutrition, Food and Exercise at the College of Agriculture and Virginia Tech Life Sciences, began the five-year study by examining changes in brain chemical levels after a prolonged period of cocaine withdrawal.
Scientists focused on the ventral pallidum, a tiny “stepping stone” region of the brain that connects the cortical, tonsil, and striatal circuits, making it an anatomical hub for encoding rewards, Shin explained. The researchers found that cells in this area of the brain expressed extremely high levels of a certain protein, the dopamine D3 receptor (DRD3), two weeks after quitting the cocaine.
“This change in brain chemistry was not immediate,” Shin said. “DRD3 production only increased after prolonged abstinence, which was a compelling finding. This has led us to ask ourselves: what cells express this protein and where in the brain do they connect? “
Using a harmless virus to light up a neural path, the researchers revealed two locations where these cells connect after leaving the ventral pallidum: the lateral habenula and the ventral tegmental area. Shin developed a genetic precipitation system, targeting a specific molecule, and closely monitored rapid changes in calcium levels in living neuronal cells, allowing him to detect dynamic changes in cellular activity. By combining these techniques, Shin and the other researchers individually compared how these two circuits influence drug discovery and how DRD3 contributes to brain circuitry function.
When the researchers blocked the DRD3-expressing neurons connecting the ventral pallidum and the lateral habenula, the mice lost interest in cocaine.
Cocaine is a dopamine reuptake inhibitor, which means that it floods the brain with dopamine by preventing cells from reabsorbing excess dopamine. Previous studies have shown that psychostimulants, such as cocaine and amphetamines, increase the expression of DRD3 in several regions of the brain, both in humans and in animals. But this study identifies a specific DRD3 circuit that appears to directly regulate relapses and drug-seeking behaviors after a period of abstinence.
“More research is needed, but modulating activity in this specific brain circuit may be effective in preventing drug relapses,” Lim said.
Pribiag, H., et al. (2021) The DRD3 ventral pallidum potentiates a pallido-habenular circuit leading to the release of dopamine and the search for cocaine. Neuron. doi.org/10.1016/j.neuron.2021.05.002.