Chronic morphine exposure has the opposite effect on the brain compared to cocaine in mice, providing new insight into the basis of opiate addiction, according to Mount Sinai School of Medicine researchers. They found that a protein called brain-derived neurotrophic factor (BDNF), which is increased in cocaine addiction, is inhibited in opioid addiction. The research is published in the October 5 issue of Science.
"Our study shows that BDNF responds completely differently with opioid administration compared to cocaine," said Ja Wook Koo, PhD, Postdoctoral Fellow in the Department of Neuroscience at Mount Sinai School of Medicine. "Morphine creates reward by inhibiting BDNF, whereas cocaine acts by enhancing BDNF activity."
BDNF is key to several functions in the brain and peripheral nervous system, notably for making new nerve cells and helping the survival of existing ones. It is also known to activate reward centers in the brain. Cocaine causes an increase in the presence of BDNF in a reward center of the brain called the nucleus accumbens, which results in activation of the reward center.
In the current study, the research team found that morphine suppresses BDNF in a different reward center of the brain known as the ventral tegmental area (VTA), in order to achieve reward and chronic addiction. The morphine caused a depletion of BDNF in the VTA of mice, which activated the reward centers. However, when BDNF was administered to the VTA of mice, it inhibited that reward. When BDNF was administered to the nucleus accumbens, there was no reward.
When researchers analyzed morphine-induced changes in gene expression in the nucleus accumbens, the area of the brain in which morphine caused no reward or response they found that two genes, sox11 and gadd45g, mediated the brain's response to morphine, preventing any reward and addiction.
"This study provides important insight into the molecular basis for morphine addiction, and is the first to show that BDNF is a negative modulator in brain, especially in opioid addiction, unlike stimulant addiction," said Dr. Koo. "While further research is needed, the genes we identified may be useful targets in preventing addiction." Continuing to study the counteractive response of BDNF in morphine as compared to cocaine may also help researchers determine how poly-drug use may impact the brain.
Dr. Koo is part of the Eric Nestler, MD,PhD laboratory at Mount Sinai School of Medicine. Dr. Nestler is the Nash Family Professor and Chair of Neuroscience and Director of the Friedman Brain Institute at Mount Sinai. Students in the Mount Sinai Graduate School of Biological Sciences also participated in the research, including Haosheng Sun and Diane Damez-Werno.
This study was supported by grants from the National Institute on Drug Abuse and a Rubicon Grant from the Dutch Scientific Organization.
Mount Sinai Medical Center