Let’s say you were trying to develop a new antidepressant. Then you’d need a screen to know if your compound or cocktail of compounds was working. Eventually, you’d be doing that screen in humans – give some depressed people your medicine, see if they feel better, see if they feel better than they would’ve felt if you’d given them a previously existing medication.
But before you get that far along, you need to have some indication that the trail you’re following leads somewhere. Earlier along you use animals.
The most common assay (that I’ve read about, at least – I have no expertise in antidepressant screening, and possibly the information I’ve read is already out of date) is the “forced swim test.” You take a depressed mouse… well, the mouse isn’t actually “depressed” – to quote a review by Petit-Demouliere et al., “Depression is defined clinically as a pathological complex of psychological, neuroendocrine and somatic symptoms that cannot be reproduced in animals and especially in mice.” – the mouse simply exhibits depression-like symptoms because you’ve subjected it to some unpleasant circumstances. Probably you would use chronic mild stress, where there is a constant aggravation like the scent of cat urine, or loud noises, or cohabitation with a bigger, meaner mouse, and that’ll result in ahedonia, a drop in dopamine levels such that activities that should be pleasurable no longer result in pleasure (see this reference, p. 66-68). Which is basically the inverse of what you’d see if you were giving your mice marijuana – that increases dopamine, so that pleasurable activities seem even better.
At any rate, you put your mouse into a cylinder of water, leave it there for a while, then quantify how much of the time it’s struggling, trying its best to survive or escape or whatnot, versus how much of the time it’s inactive, listlessly floating in dead mouse’s float.
And this turns your depression – I feel bad, life isn’t fun, every pleasure seems muted – into a number! Well, not “your” depression. The mouse’s depression. The mouse’s whatever-it-is that exhibits depression-like symptoms such as ahedonia. Whatever. The fact that it’s quantifiable means you can screen drugs – and indeed, the vast majority of antidepressants that are effective in humans also reduce the percentage time that a mouse is inactive in the forced swim test.
Sure, sure… but perhaps you’re wondering, “I’m not screening a new antidepressant… and if I was, I wouldn’t get advice from *you* about how to do it. So why are you writing all this about dropping mice into buckets of water?” Well, because I recently read a volume of Ross Gay’s poetry (to me, it’d be super scary to title a poem “Within Two Weeks the African American Poet Ross Gay Is Mistaken for Both the African American Poet Terrance Hayes and the African American Poet Kyle Dargan, Not One of Whom Looks Anything Like the Others” because I’d be worried, can I ever write something that’ll live up to that killer title? But that poem was good – I don’t think he let his title down) and a passage immediately brought to mind the forced swim test. From Ross Gay’s “The Syndromes: The Burden”:
Aside from persistent fiddling with one’s collar, the afflicted tend not to present any exterior manifestations of the Burden: no weight gain or change of posture. Therefore, in differentiating from depression or a compressed spine, the most effective diagnostic tool is the swimming pool, in which the afflicted will rapidly sink.
I wonder if his syndrome afflicts mice. If, perchance, researchers employing the forced swim test sometimes had to discard aberrant data because the mice were sinkers, obfuscating whether they would’ve otherwise struggled to survive.
Perhaps, if you were working with a population of mice thus afflicted, you’d just modify the forced swim test to use a more dense medium than water. And measure how long the mouse struggles before slipping under, say, the brine, or the 40% sucrose, or the mercury (I don’t know how heavy the burden is perceived to be, so I’m not sure how dense your test solution would need to be).
Frank Brown Cloud 