Posted March 3, 2008

Drug reduces cocaine withdrawal symptoms in preclinical trial

Compound blocks brain receptor causing anxiety and depression

Many people who've kicked the cocaine habit relapse due to anxiety and depression during withdrawal. Oftentimes, the antidepressants currently available fail to effectively battle these symptoms.

In preclinical trials, Temple researchers have found that they could reverse these symptoms through a drug, SNC80, which targeted a specific brain receptor, the delta opioid receptor. The findings appear in the February issue of Neuropharmacology.

“We were able to show that a dysfunction in the delta opioid system may have caused anxiety and depression during cocaine withdrawal. Drugs that act on this system have been shown to alleviate these behaviors in animal models,” said Ellen Unterwald, Ph.D., lead author and professor of pharmacology at Temple University’s School of Medicine and Center for Substance Abuse Research.

“If SNC80 or a related compound are shown to be effective in humans without unwanted side effects, clinicians could have another tool to treat mood and anxiety problems, including those that occur with cocaine use and withdrawal,” said Unterwald, who has been working in this field for more than 25 years. Her lab focuses on the neurobiological mechanisms involved in drug addiction.

There is increasing evidence that the opioid receptor system influences mood and anxiety behaviors, and that cocaine and other drugs of abuse in turn affect this system. In the study, Temple researchers measured delta opioid receptor signaling and behaviors after 14 days of cocaine administration and withdrawal.

When a drug like cocaine binds to a receptor it produces an effect, such as euphoria. Oftentimes, overstimulation of receptors in the brain (which is what happens when drugs are abused) leads to a phenomenon called desensitization, a molecular tolerance, where the effect wanes or decreases after persistent drug exposure.

“We know that cocaine can cause delta opioid receptors to become desensitized and remain desensitized into early withdrawal from the drug. If we better understand desensitization, we increase our chances of finding a medication to help alleviate human suffering,” said Shane A. Perrine, Ph.D., a corresponding author. Perrine conducted the research at Temple and is now at Wayne State University School of Medicine, Department of Psychiatry and Behavioral Neurosciences.

“We feel that SNC80 may act to decrease the mood-related cues that cause humans to relapse and continue drug use. We need to extend our research to better understand the dynamics that are involved in drug dependence and withdrawal and how the delta opioid receptor fits into the mix. In addition, we need help from medicinal chemists to develop compounds that act on the delta opioid receptor that can be used in humans,” Unterwald said.

—Written by Anna Nguyen

Other authors are Imran S. Sheikh, Chinwe A. Nwaneshiudu, Temple University School of Medicine, Department of Pharmacology; and Joseph A. Schroeder, Temple University School of Medicine, Department of Pharmacology, presently at Connecticut College, New London, CT. This work was supported by NIH/NIDA grants R01DA018326 (EMU) and T32DA007237 (EMU/SAP).