Manipulating gene expression levels in rats' brains can help to understand the causes of clinical depression, according to psychiatric research at Harborview Medical Center.
Understanding serotonin receptors
can speed treatment for depression
Depression may stem from low levels of serotonin, caused by malfunctioning components of the serotonin neurotransmitter system. In particular, the 5-HT1b autoreceptor, a cellular protein that inhibits or brakes serotonin release from nerve cells, may be excessively active in depression.
So far it has been found that among rats treated with common antidepressants like Prozac or Paxil, the receptor level decreases. However, these currently accepted antidepressants often take several weeks or longer to take effect.
Various studies are under way at Harborview to find out how the 5-HT1b autoreceptors cause depression. The latest study involves introducing extra copies of the gene for 5-HT1b receptors into serotonin neurons in the rat brain using viral-mediated gene transfer, known as gene therapy.
"This technique is a research tool that allows us to dissect the steps in the physiology of depression," says Dr. John Neumaier, a University of Washington assistant professor of psychiatry based at Harborview. After the gene is introduced, more 5-HT1b receptors are made, modeling the depressed state.
Preliminary results suggest that the rats show signs of depression in behavioral tests, and may allow new medications to be tested that may work better or faster than current medications. Neumaier is also testing combinations of medications to see whether they can reduce 5-HT1b receptors more rapidly than current antidepressants.
In animals that have been stressed by swimming in a tank of water, some learn to give up and are termed "helpless" while others keep trying to get out of the water. Neumaier has found that the 5-HT1b gene is turned up more when the animals show signs of helplessness by just floating in the water. "We want to see if we can prevent depressive behavior by studying how to prevent rats from increasing their 5-HT1b receptor levels when they are under mild stress, such as swim stress," he adds. This can be seen by how rats respond to the stress behaviorally and by measuring the 5-HT1b receptor levels.
The study is funded by the National Alliance of Research for Schizophrenia and Depression, the National Institute of Mental Health, Eli Lilly and the Royalty Research Fund of the University of Washington.