Serotonin-Deficient Mice Reveal Molecular Basis for Drug Abuse

Neurologic researchers have shown that it is possible to dissociate the beneficial analgesic effects of opiate drugs such as morphine from unwanted side effects such as tolerance, abuse, and addiction.

The key to determining the link between pain relief and addiction is the chemical compound serotonin (5-hydroxytryptamine or 5-HT). Although only 1% of the body's total 5-HT occurs in the brain, it is here that the actions of this substance are the most profound. The neurons containing 5-HT are concentrated in the raphe nuclei in the mid-brain, and their fibers project in a diffuse way to the cerebral cortex, hippocampus, limbic system, and hypothalamus as well as down the spinal cord. Changes in serotonin levels can alter mood: increases have a calming effect, relieving depression, insomnia, and irritability; decreases are associated with wakefulness and greater sensitivity to pain.

While mice genetically engineered to lack the Lmx1b gene that controls synthesis of serotonin have been available for several years, they die soon after birth and cannot be used for behavioral studies. However, in their paper in the August 27, 2007, online edition of the Proceedings of the [U.S.] Academy of Sciences, investigators from the Washington University School of Medicine (St. Louis, MO, USA) reported that they had created a line of mice lacking Lmx1b only in 5-HT-producing neurons. These animals lived to adulthood with apparently normal motor function.

"We performed a number of tests to measure the response of the mice to different opiate drugs,” explained senior author Dr. Zhou-Feng Chen, associate professor of anesthesiology and pharmacology at the Washington University School of Medicine. "In contrast to previous studies that used drugs to destroy or disable 5-HT neurons, our study provides the first genetic evidence to support the ‘classical' view that 5-HT neurons are a very important component of the neural circuits required for the analgesic effects of these drugs.”

Future work will focus on finding drugs that will suppress pain without risk of tolerance and drug addiction by acting on serotonergic neurons or opiate receptors on those neurons.

"These findings demonstrate that opiates exert their analgesic effects through a serotonin mechanism but that serotonin is not responsible for the negative, addictive side effects associated with those pain-killing drugs,” concluded Dr. Chen. "That was unexpected because serotonin has been known to interact with other neurotransmitters like dopamine or to modulate the levels of these neurotransmitters in the forebrain, which is important for reward-seeking behaviors.”


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Washington University School of Medicine