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)
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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.
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!
ReplyDeleteMy 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!
DeleteOh, 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.
ReplyDeleteI'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. ;-)
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