Why do our bodies build up a tolerance to some medications but not others?
In: Biology
Long story short, because tolerance is not some emergent property of biological systems, but rather a complex behavior that had to specifically evolve.
Some medications target systems that have negative feedback loops built into them, and those negative feedback loops are the reason for the tolerance.
And some medications target systems that do not have negative feedback loops built into them.
So to go with some analogies, a building with a thermostat that drives an HVAC system has a negative feedback loop for temperature.
If you put a space heater in that building you will see a rise in temperature for a bit, but within some operational range the thermostat will just turn up the air conditioners and the temperature will come back down. This is like the building has developed a “tolerance” for the space heaters.
If you want to permanently elevate the temperature inside that building you’d have to keep upping the number of space heaters to stay ahead of the thermostat system.
But let’s say instead of temperature we pick noise levels. You can put a radio in the building as while that radio plays music the noise level inside the building will he higher. Because the building doesn’t have any kind of negative feedback noise dampening system, it’s got no way of responding to lower the noise, so the building doesn’t develop “tolerance” for those radios.
Other buildings might actually have some feedback mechanisms in place. Maybe there is some of that sound absorbing foam and if noise levels are high the building pushes that foam out of little holes in the wall to lower the noise levels.
There’s no fundamental difference between heat and sound; it’s just that in our current state of engineering we tend to have buildings that *do* have negative feedback systems for temperature, but *don’t* have negative feedback systems for sound. And that, in turn, is driven by the fact that the environment we’re engineering for tends to have big changes in temperature and not really big changes in noise.
Well, let’s take this analogy back to the human body. There are certain systems that are “designed” by evolution to modulate in response to variations in environment. Like dopamine. Dopamine levels determine how likely you are to act on some idea that passes into your head. The higher your dopamine, the more responsive you are to things in general.
We have a really wide range of possible dopamine response because there are many pathways to dopamine release, and it has to keep us properly motivated – not too much and not too little – across a range of environments with different levels of stimulation. So there was an evolutionary advantage to developing internal dopamine regulation, i.e. to have some negative feedback to amp it up or dampen it down based on whether our environment or whatever other mechanism was bringing it up or down.
Once again, it’s not just an emergent property of the way dopamine works. Evolution had to sort of “go out of its way” to create that complex
mechanism of negative feedback. It’s a feature.
So you take a dopamine releaser like amphetamine or a reuptake inhibitor like cocaine, and this starts to trigger that feedback mechanism which decides there’s too much dopamine signaling going on and it lowers the responsiveness.
But then you take another neurotransmitter like glutamate. Well that’s been around for much longer. It’s older, evolutionarily speaking. It’s from the days when environments were less complex and you could get away with a simpler feedback mechanism.
Maybe glutamate receptors have some particular density, and then any time an organism encounters stress levels beyond some threshold, the glutamate activity just goes up permanently. It’s like instead of some “current level” of danger, the nervous system is just designed to remember the maximum level it’s ever encountered. The question is just “what’s the most dangerous situation I’ve ever been in?” and then glutamate activity goes up to match that.
So a glutamate antagonist like L-theanine doesn’t develop tolerance, because there’s no
mechanism that’s “watching” the level of glutamate activation to decide whether to upregulate or downregulate receptor density.
TL;DR: lack of tolerance is the default, and we have tolerance where there are specific feedback loops for specific homeostatic variables
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