up-front disclaimer: not all drugs work the same way. also, receptor adaptation does not apply uniformly, but really, what the hell DOES apply uniformly across biological systems? the brain is really, insanely complex and i can’t by any means explain all of that in a textbook, much less a blog post. i’m going to try to keep this to conceptual talk and broader principles using specific examples. now, let’s ride!
drugs work by altering the usual business of their targets. oftentimes, but definitely not always, that target is a receptor of some kind. we categorize the actions of the drug upon the receptor using the terms “agonist” and “antagonist”. an agonist increases the activity of the receptor- stimulating whatever intracellular action the receptor directs. an antagonist does the opposite- it silences the signals sent by the receptor. there are several descriptives in between- partial agonists only partially stimulate the receptor. in the case of receptors that are intrinsically active, the inverse agonist can decrease the signaling of the receptor to below the usual baseline signal.
results of initial use
these modifications of receptor activity can be used to correct errant pathways. say you have regular heartburn, and have decided to take an over-the-counter drug to remedy it. you might be taking something like Zantac, a histamine H2 receptor antagonist. this drug works by blocking the effects of histamine on certain cells in your stomach, and the endpoint is a reduction in acid production by the cells in question while the receptors are blocked. now you feel great! no more burning pain, you can go about your day.
one class of drug that you can get addicted to, but can get serious withdrawal from without being addicted, is the opioid drugs. oh man, do these have a reputation! think of percocet, vicodin, morphine, etc and usually images of addiction pop into people’s minds. however, these are legitimate clinical drugs with legitimate clinical uses, and with careful monitoring can be safely used. but let’s talk about the initial effects of the opioid drugs before we get too far into the next point i want to make. in general narcotics provide analgesia by agonist properties at the opioid receptors. usually, narcotic drugs are paired with a different type of pain reliever (such as ibuprofen or acetaminophen) for several reasons. primarily, these adjuvant pain relievers can act synergistically to provide increased relief. also, they are a deterrent for people looking to take a very high dose of the drug (but it still happens, sadly.)
one more example, this time another agonist. the underlying cause of Parkinson’s disease is the loss of dopamine-secreting cells in a very specific part of your brain called the substantia nigra. these cells are responsible for control of movement, and as they reach critical losses, motor control dissipates and leads to the symptoms of PD including tremors, rigidity, and dyskinesias. the first line remedy is to supply the brain with the dopamine it’s missing, in the form of L-DOPA. this is a pretty cool drug, so i’m gonna talk about it a little bit. L-DOPA is what’s known as a pro-drug, which means it becomes active only after it is metabolized. (also, it will not cross the blood-brain barrier in its metabolized form.) since we want the drug to work in the brain, L-DOPA is usually taken along with carbidopa, an inhibitor of the peripheral L-DOPA metabolizing enzyme. this ensures the drug makes it into the brain where we want it, before it gets metabolized away.
but over the long term… homeostasis!
it’s awesome that we have so many drugs at hand to alter the body’s function, isn’t it? the downside to all this is that the body is amazingly adaptable. you alter a system, the body alters it back! eventually, tolerance develops and you need more and more drug to maintain that same initial effect. but the big question i’m writing about is… WHY?
the answer is… homeostasis! let’s define. homeostasis is the tendency for the body to work toward an system-wide equilibrium, to work to maintain a stable state. that means the body will try to adapt to whatever drug you put into it to return to the state you are trying to correct.
tolerance of the receptor signaling system you’d like to manipulate can come from several different points in said system. cells are great at adapting to signal, and can alter receptors or any downstream components after the receptor.
receptor downregulation and uncoupling
one very common mechanism involved in tolerance to an agonist is the downregulation of the receptor. this can be via internalization/recycling, degradation, or alteration of production of new receptors. overall, the effect is that there are fewer receptors on the cell surface to receive and transmit the signal from the outside to the inside. the same amount of drug gradually has less effect! the cell has adapted to the increased amount of signal (aka drug) on the outside, and has adapted the processes on the inside to maintain its normal function despite the concentrations of drug out there. the reverse is true for antagonists. if the cell is not getting signaling from the receptors in question, it can increase receptors on the surface to scavenge as much signal as possible. now you need more drug to block the bigger number of receptors.
receptors can also uncouple from their signaling partners inside the cell, while remaining on the cell surface. i am most familiar with g-protein coupled receptors, so i will put them up as an example. g protein coupled receptors (which is a giant pain to type, so from here on out they are GPCRs) send their signal along to g proteins. these g proteins then stimulate (or attenuate) all kinds of other processes inside the cell. but some of the downstream steps of g proteins can temporarily alter the structure of the receptor itself (via phosphorylation and then recruitment of the arrestin protein, for example) to stop the receptor from transmitting signal to the g proteins. in this way, the receptor itself is “turned off” by the cell.
to make things even more complex (damn i love receptors), different internalization and recycling patterns of receptors emerge with different strengths of agonist! this is particularly true for my favorite receptor. when treated with a full agonist, receptors are recycled and sent right back to the membrane. partial agonist sends them to be degraded. my receptor downregulates MORE in response to a PARTIAL agonist! (this is perfectly logical when you see the science behind it, actually, and if anyone wants a deeper explanation i can provide it.)
adaptations after the receptor
cells are tricky in that they can alter production of just about any protein. so say you have a drug that triggers a decrease in adenylyl cyclase activity. (AC produces the second messenger cAMP, which gets itself into MANY signaling pathways.) the cell can just make more AC, homeostasis here we come. you see the cell means business in this whole homeostasis game. the house will not be beaten, so to speak.
the end result?
so what happens? the same amount of drug becomes less effective. that zantac might still leave you with a little bit of heartburn. the opioids don’t relieve the pain like they used to, and in desperation a patient takes a little more, a little more. (as i mentioned before, clinical use of narcotics includes close monitoring and drug holidays to give the system a chance to re-sensitize to the narcotics. meanwhile, patients are given a non-narcotic pain reliever and some anti-withdrawal drugs just in case.) the parkinson’s and L-DOPA case, well, that’s far more complex than a simple drug-receptor interaction. presence of dopamine leads to negative feedback- cells that are still alive and releasing dopamine start to release less of it. this, as you can imagine, only exacerbates the problem in the long run.
and getting back to withdrawal…
so now we’ve covered a LOT of ground. this is a far longer post than i expected to write! and let’s circle back to the original question: why do we have withdrawal symptoms, and why are they not a sign that you are addicted to the drug you just stopped taking?
after your cells have had some time to adapt to the presence of that certain concentration of drug you’ve been taking, they are basically optimally positioned for existence in that particular chemical environment. but you decide to stop taking the drug and remove the chemical, and pow! the cells have to re-adapt again. cells don’t usually accomplish this in an immediate manner. it takes time for the changes in signaling to instigate change in the cell’s protein composition (and therefore, function!) remember, these receptors all have their very own normal jobs to do, and what we’re doing is basically interfering with that to produce our desired effect.
sometimes this amounts to some very strong effects. when a longish-term vicodin user stops taking vicodin, for example, the opioid receptors have desensitized and downregulated so that it takes a presence of a certain amount of drug to perform the normal opioid receptor functions. suddenly, that drug is gone! receptors are not very sensitive anymore, and the amount of endogenous opioids (that is, endorphins) is not nearly high enough to maintain that new “normal” level of function! now you get the withdrawal effects as the opioid system can’t maintain its usual level of function- which includes regulation of digestion and breathing, among MANY other things. narcotic withdrawal is pretty extreme, and withdrawal from other drugs won’t necessarily be as horrible. (caffiene withdrawal, for one, is associated with nasty headaches, but i’ll take that over narcotic withdrawal.)
so withdrawal is a consequence of tolerance, and tolerance is a consequence long-term presence of a drug in your body and your cellular adaptations to it. these are all perfectly usual responses to the fact that you’re altering your body’s normal chemistry to cause a desired effect, and do not necessitate that you have developed the disorder of behavior known as addiction.
unfortunately, i have missed a lot (there is much to discuss!) but this is a very long post already, and i hope it is informative in its own right.