How do drug users gain tolerance for a drug?

[confusedbyphysics]

We're studying cell signaling and signal transduction in my biology class, and we discussed this briefly in class but I don't really understand it.
Why does the affect of a drug decrease the more a person uses it?
I don't understand. If someone takes a drug more, wouldn't there be more of the drug in the cells, thus increasing the effects of the drug?
Sorry if this is a stupid question, but thanks for anyone that can help me understand.

 

[quasi426]

I don't know the exact mechanism down to the molecular level, but essentially sometimes the receptors on the nerve membranes that bind the active compounds released by the drug are down regulated. One way of doing this is via endocytosis, which means that a piece of the membrane with the receptors, which usually are transmembrane proteins, is pinched off and taken into the cell. Then you get less receptors on the membrane and thus less sensitivity to the active compounds of the drugs. I didn't include any specific names of any proteins or a specific example. But if someone else knows a specific example I would like to read about it as well.

 

[bort]

One specific example is in the addiction to opiates. In the locus ceruleus, it appears that the opiate receptors do get down-regulated. This process is called desensitization, meaning that the neurons are now less sensitive to the same amount of drug. However, it appears more complicated than simple down-regulation of opiate receptors. The high levels of drug lead to a lot of stimulation of the cells which in turn actually physically changes the neurons. As far as I know, this is still a well studied problem.

 

[quasi426]

So something inside the cell is happening as well? Maybe in the signal transduction pathway, something is getting expressed less/more or something new is getting expressed. I'm just speculating.

 

[chantella28]

this is kind of ironic... i read this question last night and then my prof talked about this in class today

Drug tolerance has to do with the smooth endoplasmic reticulum in cells. The smooth E.R. takes insoluble substances and through hydroxylation reactions (changing molecular oxygen to generate hydroxy groups) they turn insoluble substances into soluble substances.

The smooth E.R. rapidly proliferates to get rid of the toxic substance and so the next time the drug is given, there is more smooth E.R. so it can get rid of the substance more quickly thus more is needed to create the same effect.

The main concern with this and long term drug use is that via the hydroxylation reactions, carcinogenic (cancer causing) byproducts can be formed...

 

[Moonbear]

this is kind of ironic... i read this question last night and then my prof talked about this in class today
Drug tolerance has to do with the smooth endoplasmic reticulum in cells. The smooth E.R. takes insoluble substances and through hydroxylation reactions (changing molecular oxygen to generate hydroxy groups) they turn insoluble substances into soluble substances.
The smooth E.R. rapidly proliferates to get rid of the toxic substance and so the next time the drug is given, there is more smooth E.R. so it can get rid of the substance more quickly thus more is needed to create the same effect.
The main concern with this and long term drug use is that via the hydroxylation reactions, carcinogenic (cancer causing) byproducts can be formed...

That's something from very old literature, and, as far as I know, only applies to alcohol effects on liver cells. The liver increases production of alcohol dehydrogenase (a mechanism involving the smooth ER), which helps to metabolize the alcohol faster. But that's not truly tolerance as much as more rapid clearance to keep blood concentrations of ethanol lower.

Drug tolerance, where higher doses reaching cells have less effect on the cells, as occurs in the process of addiction, is related to the availability of the receptors for that drug. As has been described above by others, part of the mechanism for tolerance is at the level of receptor availability, such as via a change in the rate of receptor internalization, recycling, or de novo synthesis. There may also be a change in how the signal transduction pathways respond following receptor binding. So, it's certainly not a simple process. Understanding this is not only important for treatment of addiction, but also for preventing tolerance/addiction in patients being treated with drugs for reasons such as pain management.