More of an understanding as to how re-uptake inhibitors and MAOIs work

[red22]

I'd like more of an understanding as to how re-uptake inhibitors and MAOIs work. No description I've ever seen has ever had a context, which makes them poor quality descriptions to me. What I mean by context is that the descriptions I've seen describe a cycle of re-uptake (re-uptake inhibitors) or destruction (MAOIs) and these descriptions never fully establish the difference between these cycles in the non-drug state versus the medicated state. How many of these "birth and death" cycles (generation of chemicals followed by destruction or uptake) does a sober person have? How many of these cycles does a drugged person have? Going off the terribly inadequate descriptions, I can only assume that a non-drugged person has many of these cycles, with interims where their synapses are filled with the lovey-dovey chemicals, whereas the drugged person has artificially extended interims where the synapses are filled, and consequently less cycles in a 24 hour period. Of course, this description insinuates that a person's state of conciousness consists of mood swings -- even when on the drugs, albeit less so -- and that just can't be right. But alas when all you fucking give a person is "enables dopamine to stay in the synapse longer" one can only make a series of guesses as to what is actually fucking going on. I need details, I need context.

 

[sekio]

Reuptake and destruction of monoamine neurotransmitters does not occur in "cycles". They are both processes that occur in the body independent of each other.

The main way your body recovers dopamine is by reuptake. Probably more than 80% of dopamine is recovered this way, so as to not be wasted with the massive turnover. The half life of dopamine is very short in the synapse, between 0.2-2 seconds depending on location in the brain, and ~1 minute in the blood. Not all cells have the same amount of dopamine transporter proteins, in fact some don't have any, and dopamine is in solution after it's been released into the synapse, so it can diffuse into the blood or other tissues. This is where MAO comes into play, it scavenges any dopamine that the transporters miss, so you don't have excess dopamine triggering your receptors all the time, or ending up in cells where it should not be. Small amounts are metabolised to other compounds like O-methyldopamine, norepinephrine, etc as well, but this is less relevant in normal functioning.

(This is the same for norepinephrine and serotonin. Histamine as well.)

Your cells use dopamine to signal responses to short-term events, so the dopamine has to be degraded pretty quickly or it becomes useless for short-term signalling. Dopamine is being released all the time, even in depressed people. If you had no dopamine release going on, you would be essentially Parkinsonian, unable to move and probably totally loopy, because it's important for the regulation of movement and mood.

Your dopamine transporters are working 24/7 to keep the synapse clean of dopamine, and monoamine oxidase just get any stragglers. There is a certain "response" your cells experience when they fire a pulse, that is enhanced by reuptake inhibition. Because the dopamine stays in the synapse longer. Because it can't be removed by the transporters.

MAO inhibition is a little more complex because it also blocks the major route of breaking down some minor "trace amines", which are also mood modifiers, and overall reuptake inhibition has much more of an effect on dopamine levels than MAO inhibition does. But it still effects monoamine levels, just in a different way than reuptake inhibitors do.

Depression is not as simple as "having too much/not enough dopamine/serotonin". It's also about where that dopamine or serotonin is, and what's happening to the cells around it.

 

[Seppi]

Adding on to what Sekio mentioned, the truth is, we (humans, collectively) are still learning about additional, novel mechanisms of reuptake inhibition as more is learned about GPCRs/LGICs.

Most people are unaware that amphetamines and trace amine operate through TAARs or that St John's Wort/Hyperforin inhibits monoamine reuptake + gaba/glutamate reuptake via TRPC6. There's undoubtedly going to be even more neuromodulatory systems discovered as research progresses.

So...I actually think a bottom-up approach is better than a top-down approach when learning molecular neuropharm. (IE learn about receptors and specific drugs rather than entire drug classes (newer receptor classes sometimes undergo rapid change [ex: TAARs and CACCs] - older ones are usually stable). There's often pathological cases in drug classes that invalidates generalizations people make about them, like reuptake inhibitors and my 2 previous examples or tricyclic antidepressants and Tianeptine + Opipramol having unique+entirely different mechanisms of action.

My advice is just build up a general understanding by reading wikipedia articles on those topics and buying a general reference text (I mainly use this textbook) for additional background.

 

[red22]

Thank you, guys! I'm going to have to read the info over a few times.

Seppi, I had actually already downloaded that book a while ago. Heh. I guess to truly understand this stuff, you have to read a book like that.