A new study from researchers at Duke University in Durham, NC, finds that mice deficient in serotonin are more vulnerable to social stressors than a group of healthy control mice.
Low serotonin levels have traditionally been suspected as playing a role in depression, but there has been little solid evidence to support this hypothesis. Consequently, scientists have been increasingly moving away from the low-serotonin theory and looking instead at other possible causes of depression, such as the relationship between stress and inflammation and other environmental factors.
Last September, Medical News Today reported on a study published in ACS Chemical Neuroscience that found no difference in behaviors between mice that lacked serotonin and a normal group of control mice.
From this finding, the researchers behind that study - from Dingell VA Medical Center and Wayne State University School of Medicine, both in Detroit, MI - concluded that serotonin may not be a dominant factor in depression. Instead, they suggested that risk for the condition may instead be comprised of a range of different factors.
However, the Duke paper - which is published in the Proceedings of the National Academy of Sciences - reports opposite findings to that study.
Senior author Marc Caron, the James B. Duke professor of cell biology at the Duke University School of Medicine and a member of the Duke Institute for Brain Sciences, explains:
"Our results are very exciting because they establish in a genetically defined animal model of serotonin deficiency, that low serotonin could be a contributing factor to the development of depression in response to psychosocial stress - and can lead to the failure of [selective serotonin reuptake inhibitors] to alleviate symptoms of depression."
In their study, the Duke researchers used a transgenic mouse strain - Tph2KI - bred to have only 20-40% of normal serotonin levels.
The team exposed the mice to stress by briefly housing them with an aggressive stranger mouse every day for 7-10 days. To test for depression-like behaviors, the researchers then examined whether the test mice would avoid interacting with the stranger mouse.
The control mice did not exhibit these depression symptoms after a week of social stress, but the serotonin-deficient mice did. Both groups eventually displayed depression-like symptoms following longer periods of stress exposure.
The mice with depression-like symptoms were then treated with Prozac for 3 weeks. Although the normal mice saw reduced depression symptoms following treatment, the Tph2KI mice did not.
Because Prozac is a selective serotonin reuptake inhibitor (SSRI) and works by blocking cells' ability to "recapture" serotonin, Prof. Caron says it makes sense that the antidepressant would be less effective in animals that have low levels of serotonin.
The researchers think this might explain why some depressed people are unresponsive to treatment with SSRIs.
The lateral habenula as drug target for treatment-resistant depression
A brain region called the lateral habenula has been investigated by some studies as a potential drug target for treatment-resistant depression. The lateral habenula is also known as the "punishment" region of the brain, and scientists think that an overactive lateral habenula may trigger depression.
To investigate this, Prof. Caron's team targeted the lateral habenulae of the mice with "designer receptors exclusively activated by designer drugs." (DREADDs) - designer drugs that control the activity of specific neurons.
The scientists found that by inhibiting neurons in the lateral habenulae of the Tph2KI mice using the DREADDs, they were able to reverse the social avoidance behavior of these mice.
Although this is a promising first step in identifying targets for treatment-resistant depression, the researchers say that DREADDs are not appropriate for use in humans.
"The next step is to figure out how we can turn off this brain region in a relatively non-invasive way that would have better therapeutic potential," says lead author Benjamin Sachs, a postdoctoral researcher in Prof. Caron's group.
An additional finding from the research was that the serotonin-deficient mice produced a signaling molecule - β-catenin - in different areas of the brain to the normal mice when they were exposed to social stress.According to Sachs, this suggests that serotonin deficiency may block a protective pathway that includes β-catenin:
"If we can identify what's both upstream and downstream of β-catenin, we might be able to come up with attractive drug targets to activate this pathway and promote resilience."