12 ms·

> Amphetamines push catecholamines out of presynaptic neurons; that’s pretty settled. Sure, I am not doubting that we have some understanding of some of the me

> Amphetamines push catecholamines out of presynaptic neurons; that’s pretty settled. 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.?

serf 2y ago
>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.? 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.
- gruez 2y ago
  That doesn't explain why SSRIs take weeks to work, rather than hours/days.
  - solumunus 2y ago
    They were talking about amphetamines.
  - Jarwain 2y ago
    My understanding is that with SSRIs it's not the drug itself that helps but rather the repercussions of developing a "tolerance" to the drug. 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.
    - alan-hn 2y ago
      Is the overload of presynaptic serotonin receptors that ends up causes endocytosis of those very receptors. The purpose of these receptors is to help regulate vesicular release of serotonin into the synapse by shutting down release when too much is detected. Less of those receptors means more serotonin in the synapse after long periods of treatment. The current overall theory (iirc) is that this helps to drive BDNF upregulation which is a neuronal growth factor that helps to drive more dendrite and bouton formation leading to new and more robust network connections
- bhouston 2y ago
  > those disorders are often characterized by inappropriate dopamine/norepinepherine levels. 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.
- hirvi74 2y ago
  > those disorders are often characterized by inappropriate dopamine/norepinepherine levels. 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?
butlike 2y ago
I was under the assumption norepinephrine was the desired neurotransmitter for ADHD patients, but in order to cross the blood-brain barrier, it needed to be attached to dopamine. 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?
- alan-hn 2y ago
  Norepinephrine is released from neurons both in the brain and in the peripheral nervous system, it is the drug that crosses the blood brain barrier not norepinephrine. 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. https://en.m.wikipedia.org/wiki/Neuron https://en.m.wikipedia.org/wiki/Neuron https://en.m.wikipedia.org/wiki/Synapse https://en.m.wikipedia.org/wiki/Synapse
Arch485 2y ago
Well, one reason we don't know why SSRIs give therapeutic relief is because they don't, actually! 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.
- arthur2e5 2y ago
  We do know that for the lucky ones on which SSRIs do work, it seems to reverse some of the brain structure changes associated with depression -- some abnormally small parts tend to grow thicker. The reversal can be seen at one week after the start of medication use, before one can even tell whether an antidepressant has started working (a commonly-cited duration would be 2 weeks). [1]: https://www.nature.com/articles/s44220-023-00187-w https://www.nature.com/articles/s44220-023-00187-w

serf 2y ago

>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.? 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.

gruez 2y ago
That doesn't explain why SSRIs take weeks to work, rather than hours/days.
- solumunus 2y ago
  They were talking about amphetamines.
- Jarwain 2y ago
  My understanding is that with SSRIs it's not the drug itself that helps but rather the repercussions of developing a "tolerance" to the drug. 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.
  - alan-hn 2y ago
    Is the overload of presynaptic serotonin receptors that ends up causes endocytosis of those very receptors. The purpose of these receptors is to help regulate vesicular release of serotonin into the synapse by shutting down release when too much is detected. Less of those receptors means more serotonin in the synapse after long periods of treatment. The current overall theory (iirc) is that this helps to drive BDNF upregulation which is a neuronal growth factor that helps to drive more dendrite and bouton formation leading to new and more robust network connections
bhouston 2y ago
> those disorders are often characterized by inappropriate dopamine/norepinepherine levels. 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.
hirvi74 2y ago
> those disorders are often characterized by inappropriate dopamine/norepinepherine levels. 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?

butlike 2y ago

I was under the assumption norepinephrine was the desired neurotransmitter for ADHD patients, but in order to cross the blood-brain barrier, it needed to be attached to dopamine. 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?

alan-hn 2y ago
Norepinephrine is released from neurons both in the brain and in the peripheral nervous system, it is the drug that crosses the blood brain barrier not norepinephrine. 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. https://en.m.wikipedia.org/wiki/Neuron https://en.m.wikipedia.org/wiki/Neuron https://en.m.wikipedia.org/wiki/Synapse https://en.m.wikipedia.org/wiki/Synapse

Arch485 2y ago

Well, one reason we don't know why SSRIs give therapeutic relief is because they don't, actually! 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.

arthur2e5 2y ago
We do know that for the lucky ones on which SSRIs do work, it seems to reverse some of the brain structure changes associated with depression -- some abnormally small parts tend to grow thicker. The reversal can be seen at one week after the start of medication use, before one can even tell whether an antidepressant has started working (a commonly-cited duration would be 2 weeks). [1]: https://www.nature.com/articles/s44220-023-00187-w https://www.nature.com/articles/s44220-023-00187-w