Depression Post 3: Studying Depression in the Lab

Welcome to depression post three!  Previously I covered the symptoms and etiology of depression, and some of the most common antidepressant medications and how they work.  Now I’d like to go into some of the research behind it.  After all, it’s not like we just grab a depressed person and say “here, take this and call me in the morning”.  Every  new drug that comes out on the market has to go through rigorous clinical testing to determine whether or not it works, and just as important, whether or not it is safe.  And even then, drug companies and the FDA make mistakes.

This post (to save me writing another 2,000 words at a time) is going to focus on the way we study depression (along with other psychiatric disorders) using animal behavioral models, particularly rodent models. But of course, you can’t put a mouse on a couch and ask it how it feels about its mother. What researchers have found is that there are ways of studying the efficacy of traditional antidepressants. So rodent tests for depression are not so much tests for depression so much as they are screening for possible antidepressant therapies.

Tests of Antidepressant Efficacy

1) Forced Swim Test: Take a mouse (or rat), put it in a bucket of water where it has to swim. Wait, and ponder how there is noting quite so cute as a mouse swimming. Pretty soon the mouse will give up when it realizes it can’t get out, and start floating in the water. The time it takes to give up is estimated as the time it takes for the mouse to despair. Researchers have found that antidepressants like Prozac or Celexa increase the amount of time that the mice spend swimming and trying to get out of the bucket. So you can screen for an antidepressant and whether or not it will work by giving to a mouse in the forced swim test.

2) Tail Suspension Test: This time, string the mouse up by its tail. Wait for the mouse to stop wriggling around. It will give up pretty soon (though it’s best to use fat mice for this, skinny mice can climb their own tails and so are no good). This is just like the Forced Swim Test, and works pretty much the same way.

3) Sucrose Drinking: This test measures anhedonia, or whether or not animals are sensitive to pleasurable stimuli. And the mice love it! Take a mouse and give it a choice between water, and a sweet solution like sugar water, Kool Aid, or Tang (you would be AMAZED at the number of scientific studies that use things like Tang). Obviously the mice like the sweet stuff better, and how much MORE they like it (how much they drink) is a measure of anhedonia. So you can take mouse models of depression and see if they drink sugar water, then give them antidepressants and see if they drink more.

So how do you get depressed mice in the first place?  First of all, some strains of mice or rats are more sensitive to depression than others, or more sensitive to antidepressants.  So once you’ve picked your strain, you then have several options:

1) Parental Separation:  taking a mouse (or a rat, or a monkey) away from its mother for a while (either raising it on a cloth surrogate or for rodents, just taking it away for an hour a day), can produce mice that are more sensitive to stress and give up swimming more easily.

2) Social Defeat:  Put a mouse in a cage with a bigger mouse.  The small mouse (or the non-resident mouse, mice are very territorial) will lose the fight.  If you have a mouse lose a fight several times, they start to get depressed.  In monkeys, if you put monkeys in groups, there is a hierarchy that is soon established.  The monkeys at the bottom of the heap show signs of depression and are sensitive to antidepressants.

3) Chronic Stress: Put a mouse in a cage, and put that cage in a rat cage.  In the wild, rats eat mice, so even just the smell of them can stress out a mouse.  A lot of times you can just put a piece of bedding that’s been in a rat cage in a mouse case, or something that smells like cats, etc.  If you keep it in there for several days, you get a chronic model of stress, and the mice that have been stressed have very different reactions in the depression tests.

Those are some of the most well known models of depression and behavioral tests for antidepressant efficacy. Of course there are also genetic models (with different versions of the serotonin transporter), and there are ways to look at animals with depressed phenotypes using PET imaging and MRI. Next up, the serotonin hypothesis of depression, and why it’s probably a lot more complicated than that.

8 Responses

  1. And, apart from the mice, big models in this research are lobsters and crayfish – losing a fight induces “depression” reversible by serotonin, Prozac, etc.

  2. Good read, but have you read the new research that suggests anti depressants actually work via healing damaged neurons rather than resetting chemical imbalances in the brain. Makes drugs like Zoloft seem far more palatable.

  3. Depressed Man: Yes, I have seen that research, and I think there’s a lot to it, especially the work done with BDNF. Those drugs being tested also show similar results in behavioral testing. The testing is, after all, looking at efficacy of anti-depressants rather than mechanisms. But the neuronal-growth work is expanding rapidly, and I think it holds a lot of promise.

  4. There is a more pernicious form of the rat/mouse swim test, where a weight is attached to the animal, and they cannot simply float. They must swim or drown. Mice/rats were submitted to this in the past to near drowning daily but rescued for days on end. Obviously they tried to bite their tormentors after a very short while. As time went on, some drowned in water, some died in the cage before the next days swim, and some survived the concentration camp. All were autopsied. The drowned and the survivors all had markedly hypertrophied (enlarged) adrenal glands. The ones “found dead in bed” had bilateral hemorraghic (sp) failed adrenal glands having died of acute adrenal failure. I learned this in med school or later during internship/residency. I felt like the rats. I would weep at times. If anybody can find an article or book documenting my memory I would appreciate it

  5. Michael: I can assure you that we would NEVER do something like that these days. I was horrified just to hear that some people keep their animals in the water longer than 5 minutes. We only do about 2 minute segments, and the animals are dried off afterwards to minimize stress. We’d also never run them for more than three days, total, it’s too much stress. I don’t know the study that you’re talking about, but it sounds more like a horrendous stress study than any kind of depression study.

  6. We still need to work on our depression rat model. FST is a good approach, but we must keep in mind that other than assessing the effectiveness of antidepressants, is not very reliable. Wistar-Kyota rat strain seems promising as a model. The model must have atrophic hippocampi, fear sensitization, and succesfully learn helplessness.

  7. Wow. that rat experiment sounds pretty horrible. How can they prove that the rat stops swimming out of hopelessness as opposed to sheer exhaustion?

    Thanks for sharing this study. Pretty interesting.

  8. I follow your posts for quite a long time and should tell you that your posts are always valuable to readers.

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