Here’s a fun one: we don’t know how general anesthetics work. From ether to desflurane to propofol, they all exhibit similar behavior, but we actually don’t know exactly what that mechanism is.
Anesthesia is weird. I'm an anesthesiologist; believe me, there are tons of weird things about the human body that you learn from throwing various compounds at bodies and seeing what happens. Xenon is an effective (though expensive) anesthetic gas by itself. People of West African descent occasionally (~10-20%, usually on the lower end of that) have a hypersalivatory response to cholinergic stimulation. Drugs that should be fine and got approved but turn out to kill kids disproportionately (rapacuronium).
Much of our practice is derived from "we've been doing this without too many bad effects for a long time with these drugs, so we're going to continue using them rather than try something new unless the new one brings something to the table that's a slam-dunk". Diethyl ether is slow, it smells awful, and it's flammable (and will form explosive peroxides if stored too long), but it's still a good anesthetic. If I had to re-create civilization from scratch, that would be one of the first drugs I tried to make.
In the days before routine pulse oximetry (which, in addition to measuring oxygenation of the blood, is proof of a pulse - it does not work on heart-lung bypass), the fact that the heart was beating was confirmed by using an esophageal or precordial stethoscope. This was typically connected to an earpiece that was molded to the individual user by a simple piece of tubing. Precordial stethoscopes are a neat thing to see; they are just the "bell" part of a stethoscope made out of a decent-sized piece of metal so that the weight would keep it on the patient's chest and prevent it from moving around. I'm told that anesthesiologists who practiced in this era, which was also before each anesthesia monitor had continuous gas sampling of the patient's respirations to determine the concentration of anesthetic agents, could recognize when a patient under halothane (which was also a well-known cardiac depressant, but unlike many other agents had a non-irritating smell and so could be used for pediatric cases without an existing IV, where anesthesia is induced by simply breathing the gas) was getting too deep by the change of the heart sounds. We have a newer, less cardiac-affecting anesthetic now, sevoflurane, which has essentially replaced halothane in developed countries and I would assume most less-developed ones as well (because it's now off-patent and pretty cheap).
Sure, I am not doubting that we have some understanding of some of the mechanisms. We know SSRI's affect serotonin, but not how they work in terms of providing therapeutic relief. My point about amphetamines was the same. We might know that catecholamines are pushed out of the presynaptic neurons, but how/why does that treat conditions like ADHD, Narcolepsy, Binge-Eating Disorder, etc.?
There has been no clinical evidence on SSRIs mitigating the effects if clinical depression, and a lot if anecdata I've seen is that they're very hit-or-miss.
This makes the effects of extra dopamine in the system a side-effect, not the feature. But I'm not a doctor, so I could be wrong on that.
Could it be that catecholamines have a higher affinity for the presynaptic neurons, so we need the dopamine to push it out, at which point there's a chance the norepinephrine can get into the receptor?
NE may be desirable in some subtypes of ADHD because varying mechanisms can cause the same symptomology, its complicated and we don't know enough yet. Dopamine also plays an important role in attention
In no way does dopamine "attach" to NE, so I'm not sure what you're trying to say there
There are receptors for catecholamines both pre and postsynaptically, so it is a misstatement to say that they have an affinity for one or the other.
The way that synaptic release works is generally through vesicular release but in the case of amphetamines what they do is not only stop the reuptake of dopamine or NE from their synapses but they can also cause efflux out of the reuptake transporter.
Generally speaking NE and dopamine are in different neurons but there may be some crossover.
those disorders are often characterized by inappropriate dopamine/norepinepherine levels.
if you push more catecholamines into availability, while also reducing the ability for them to be re-uptaked by their associated transport chains, then the patient begins to edge towards a more normal saturation level of the deficit chemicals.
Those are secondary effects of underlying issues in ADHD, Binge-Eating, etc. The core issue is something not working well, such as in ADHD, the brain may have smaller prefrontal cortex regions (or less connected, etc) and thus have problem with self-regulation. You can sort of work around this by boosting dopamine, but it is working around the issue.
It is akin to an engine that is under powered so we figure you show to press the gas pedal harder (dopamine increases focus/effort/alert, so it is like pressing on the gas.) But the core issue is that the engine is underpowered in comparison to others. And it may be underpowered for a large variety of very specific reasons, including genetics (controlling development, or resistance to stressors), physical trauma, sleep, etc.
My understanding is that is still hypothetical at this point, albeit the leading hypothesis. Personally, I think that ADHD is just an abstraction for a set of behaviors. I am not trying to downplay its severity, it's caused me undue suffering, but my point being that I believe there are multiple etiologies that have fairly similar symptoms.
After all, stimulants have a wide variance in efficacy for people with ADHD, and there are plenty of medications that are even non-stimulants, so I think that should be a sign that there is much more to this disorder(s) than just dopamine and norepinephrine.
But hey, what do I know?
Trying to remember what a neuroscience friend of mine said; your brain, like your body, tries to reach some sort of homeostasis. Inhibiting the reuptake of serotonin results in there being more serotonin in the brain, resulting in your brain changing somehow to handle this serotonin.
These changes take time to develop, thus the delay on the impact of ssris.
Generally, consistent use of any drug will cause these longer term changes in the brain. Since your body is trying to find homeostasis, these changes reduce the impact of the acute effect of the drug, thus the experience of tolerance. The experience of withdrawal is a side effect of having these changes without the acute effect of the drug.