Tuesday, March 31, 2015

#expbio ASPET Blogging: RGS4 differentially regulates antidepressant and locomotor behaviors in vivo

Depression is one of the most common mental disorders in the United States, affecting about 7 percent of adults per year. There is a 16% lifetime prevalence for depression and 1 in 5 people in the US will experience a depressive episode in their lifetime. Many people are under the impression that the way antidepressants work is unknown but that’s not exactly true. Most currently used antidepressants affect proteins that block reuptake (Figure 1A) of chemicals called neurotransmitters (Figure 1B) back into a brain cell, called a neuron, after their release from that cell. This blockage allows the transmitter to stay active longer in the synapse (Figure 1C), which can relieve depressive symptoms. Unfortunately, there are two major issues with depression treatments, according to Dr. Jeffrey Talbot, Director of the Research Center on Substance Abuse and Depression at the Roseman University of Health Sciences.

Figure 1: Neuronal signaling. (Source: "Reuptake both" by Sabar

It takes several weeks of treatment before patients are relieved of their symptoms and many people don’t find relief even after trying several different antidepressant medications. Some also have side effects uncomfortable enough that patients stop taking them. Dr. Talbot thinks that in order to improve treatments, we need to look at other drug targets rather than continuing to focus just on blocking reuptake of neurotransmitters. These drug targets could be the proteins, called receptors (Figure 1D), that neurotransmitters bind to on other cells. Receptors are activated by neurotransmitters and cause an effect in the cell. This effect is sometimes to activate proteins called G-proteins. His lab takes an approach that is even more specific: a protein that regulates the activity of G-proteins, called Regulator of G-protein Signaling 4, or RGS4.

Previously, his lab found insensitivity to the effects of RGS proteins at the Gαi2 G-protein decreases depression and anxiety-like behavior in mice. This effect is also correlated with the expression levels of RGS4 mRNA and protein. His lab’s Experimental Biology poster examined the role of RGS4 in particular.    

An undergraduate student in Dr. Talbot’s lab, Cienna Nielsen, examined the role of RGS4 on locomotor, depression, and anxiety behaviors. She used RGS4 mice lacking the RGS4 gene, called RGS4 knockout (RGS4-KO) mice, to test two types of antidepressants in a variety of behavioral tests.

The antidepressants included fluoxetine (brand name Prozac), a serotonin selective reuptake inhibitor (SSRI), and desipramine (brand name Norpramin), which blocks reuptake of norepinephrine among other effects. Behavioral testing included the open field test to assess locomotion, as well as the tail suspension test and novelty induced hypophagia for depression behaviors. A stress-induced model of depression was also used in conjunction with the tail suspension test to study susceptibility to depression. The tail suspension test assesses motivation to escape an aversive situation (hanging by their tail). If a mouse gives up and spends more time hanging immobile it indicates depression-like behavior. Novelty-induced hypophagia is a depression test that measures how long it takes mice to enter a new environment to drink a sweetened solution. Mice that take longer to approach the drink have increased depression-like behavior. In the stress-induced model, social defeat, mice that are exposed to stress have increased depression levels as well.

There was no difference between normal, “wild type” (WT), mice and RGS4-KO mice in the time spent immobile in the tail suspension test. However, when treated with fluoxetine or desipramine the WT mice had a lower level of depression-like behavior. When RGS4-KO mice were treated with fluoxetine there was no difference in depression but there was when they were treated with desipramine. Similar results were found for the novelty-induced hypophagia experiment. Changes in locomotor activity were a different story.

There were no differences in locomotion in the open field test for WT mice treated with fluoxetine. However, both WT and RGS4-KO mice treated with desipramine showed reduced locomotion and less distance traveled in the open field test. In the stress-induced model of depression both RGS4-KO mice that did or did not receive stress were more susceptible than WT mice to depression.

Overall, Dr. Talbot says that RGS4-KO removes the response to the serotonin-based antidepressant fluoxetine but not the norepinephrine-based desipramine. This suggests that RGS4 is important for the response to serotonin-based antidepressants like fluoxetine but not through norepinephrine effects. Locomotion was reduced in KO mice after the norepinephrine-based antidepressant but not fluoxetine, but he is not sure why yet. Dr. Talbot’s research is an important step both in determining how antidepressants work and for determining potential future treatments not based on neurotransmitter reuptake. He says that RGS proteins can be “another dial to turn” when treating depression, which could help treatment-resistance patients find relief from their symptoms.


  1. I haven't gone through all of your posts yet, but have you ever researched the link between addiction & social anxiety disorder? I've read that people with the mental disorder often turn to drugs, but I've actually acquired a fear of social interactions after being in recovery for over five years. I've gained quite a bit of weight cuz I quit smoking cigarettes shortly after quitting heroin. When i know i must venture out into the world, i begin to sweat profusely, i get all flushed, i have to urinate, & my heart rate picks up. I'm just beginning my research but thought I'd ask you since i thoroughly enjoyed your scabies posts. Thank you for all you do!

    1. My area of research isn't in addiction and I haven't looked at that connection as a blog post. However, I'm sure there are labs that are studying it! A therapist would be helpful for you to address the social anxiety after addiction. I wish you the best!

  2. Oh, and I'm also having trouble finding the right meds for my depression. I've gone through three different ones in a couple of years. I'm beginning to think i need to look closer at the commercials i keep seeing about adding something to my antidepressant.

    1. I'm not a doctor so I can't help you there but my advice would be to see a doctor and not try to choose a medication yourself based on commercials. Doctors have years and years of schooling and specializations for a reason. ;-)