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Temple Researchers Show Blocking Key Brain Receptor May Reduce Anxiety during Cocaine Withdrawal

Anxiety often hinders attempts to beat cocaine addiction, and can contribute to relapse. But now, people attempting to quit cocaine may someday have an easier time during withdrawal, thanks to a novel treatment approach being developed by researchers at Temple University's Center for Substance Abuse Research.

Working with mice dependent on cocaine, scientists led by Ellen Unterwald, PhD, Professor of Pharmacology at Temple University School of Medicine and Director of Temple's Center for Substance Abuse Research, showed that by blocking the activity of a protein receptor in the brain, they can prevent anxiety during withdrawal. While the research is still in its early phase, the researchers are hopeful the work will someday lead to new therapies to help cocaine addicts successfully withdraw from their addiction. Dr. Unterwald, graduate student and first author Caryne P. Craige, and their co-workers reported their findings recently at the annual meeting of the Society for Neuroscience in New Orleans.

"Anxiety and depression are common problems among individuals who abuse cocaine and other drugs and who are trying to halt usage. This combination can be so severe and debilitating that it often drives people back to the drug again," said Dr. Unterwald. "Currently, there are no FDA-approved drugs for the treatment of cocaine addiction, and we need new ways to help people who are trying to quit. Our results might eventually help people who experience severe anxiety during cocaine withdrawal to stay clean."

Focusing on a serotonin receptor

Cocaine and other drugs of abuse increase levels of dopamine, a neurotransmitter, in the reward and pleasure areas of the brain. Neurotransmitters are chemical messengers that send signals in the brain. Similarly, levels of serotonin, a neurotransmitter involved in anxiety and depression, also rise with drug use. Dr. Unterwald noted that other research has suggested that serotonin and yet a third neurotransmitter, gamma-aminobutyric acid (GABA), may be important in anxiety related to cocaine withdrawal. She and her co-workers think that the heightened level of anxiety common during cocaine withdrawal is due, in part, to a malfunction of the serotonin and GABA systems. They focused their studies on a specific serotonin receptor, the 5-HT2C receptor.

To gather evidence for the receptor's role in the anxiety caused by cocaine withdrawal, the researchers turned to a mouse model. They gave mice cocaine three times daily for 10 days to mimic the way users take the drug. After 24 hours, they looked for withdrawal and anxiety-like symptoms using a standard measure of anxiety in rodents.

Without further cocaine, the mice going through cocaine withdrawal had increased anxiety-like behavior, akin to withdrawal symptoms in people, Dr. Unterwald said. When mice were placed on a maze that had both closed, protected areas, and open, unprotected areas, the mice undergoing cocaine withdrawal stayed in the closed areas, indicating heightened levels of anxiety. Untreated mice spent time exploring both open and closed areas of the maze. However, when the mice experiencing cocaine withdrawal were given a 5-HT2C receptor-blocking agent prior to the maze challenge, few signs of anxiety were seen.

The scientists subsequently examined the animals' brains, recording the activity of single cells from mice experiencing anxiety during cocaine withdrawal, measuring serotonin and GABA activity. GABA is an inhibitory neurotransmitter, meaning it decreases or blocks signaling in the brain. The researchers found that the mice that showed anxiety also had heightened GABA activity, suggesting that GABA was dampening serotonin and dopamine output. These results fit the team's hypothesis: anxiety during withdrawal is associated with increased GABA signaling in the brain, which functions in blocking mood-enhancing dopamine. The system that controlled anxiety was dysfunctional and not working properly.

"These results give an indication of the some of the physiological adaptations that occur during chronic cocaine exposure and which contribute to anxiety during withdrawal," Dr. Unterwald said. "We're getting a better idea of the neurocircuitry that is involved in anxiety produced by cocaine withdrawal and we can now find ways to target that circuitry."

The researchers plan to continue to study the function of the 5-HT2C receptor using various neurochemical and molecular biology techniques to see whether the receptor itself is altered by cocaine. They will continue to work with drugs that target this system and also try to learn more about stress neurocircuitry and how it contributes to cocaine addiction.

Other investigators who contributed to this work include Lynn G. Kirby, Temple University School of Medicine, and Temple University neuroscience undergraduate student Stacia Lewandowski.

The work was supported by grants from the National Institutes of Health.

Date Published: Thursday, November 01, 2012

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