Psycho-Babble Medication Thread 1110375

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Norepinehprine D4 receptor

Posted by linkadge on May 28, 2020, at 7:44:50

Apparently norepinephrine itself is a potent activator of dopamine d4 receptors. D4 receptors have been implicated in ADHD. I wonder if this is behind the efficacy of NRIs in ADHD.

https://pubmed.ncbi.nlm.nih.gov/9042615/

Linkadge

 

Re: Norepinehprine D4 receptor

Posted by undopaminergic on May 29, 2020, at 11:05:18

In reply to Norepinehprine D4 receptor, posted by linkadge on May 28, 2020, at 7:44:50

> Apparently norepinephrine itself is a potent activator of dopamine d4 receptors. D4 receptors have been implicated in ADHD. I wonder if this is behind the efficacy of NRIs in ADHD.
>
> https://pubmed.ncbi.nlm.nih.gov/9042615/
>
> Linkadge

Cite: "... noradrenaline and adrenaline exhibited a high affinity binding component (KH = 12.1 nM and 5.0 nM, respectively), similar to that of dopamine (KH = 2.6 nM), ...", and: "These results indicate that dopamine D4 receptors are activated by noradrenaline and adrenaline, although at 50-100-fold higher concentrations than dopamine.".

How do they calculate the "50-100"? 12.1 / 2.6 is ~ 4.7.

What do these affinities mean at physiological concentrations of these neurotransmitters?

-undopaminergic

 

Re: Norepinehprine D4 receptor

Posted by linkadge on May 29, 2020, at 14:38:55

In reply to Re: Norepinehprine D4 receptor, posted by undopaminergic on May 29, 2020, at 11:05:18

Yeah. Who knows how they got that number.

And as far as what the typical brain concentration of norepinephrine is...no idea.

Linkadge

 

Re: Norepinehprine D4 receptor

Posted by rjlockhart37 on May 30, 2020, at 3:15:21

In reply to Norepinehprine D4 receptor, posted by linkadge on May 28, 2020, at 7:44:50

i don't know studies and research, but i think norephirphine and dopamine, even though there different neurotransmitters, they are similar and have synergy, when NE levels are high, there is some dopamine that is activated.

 

Re: Norepinehprine D4 receptor

Posted by NKP on May 31, 2020, at 12:02:56

In reply to Re: Norepinehprine D4 receptor, posted by rjlockhart37 on May 30, 2020, at 3:15:21

That might explain why atomoxetine tends not to work immediately.

 

Re: Norepinehprine D4 receptor » NKP

Posted by linkadge on May 31, 2020, at 12:56:04

In reply to Re: Norepinehprine D4 receptor, posted by NKP on May 31, 2020, at 12:02:56

It's interesting. Atomoxetine may not work immediately, but there are reports that it can continue to work even after it is discontinued.

Linkadge

 

Re: Norepinehprine D4 receptor

Posted by undopaminergic on June 1, 2020, at 3:14:20

In reply to Re: Norepinehprine D4 receptor » NKP, posted by linkadge on May 31, 2020, at 12:56:04

> It's interesting. Atomoxetine may not work immediately, but there are reports that it can continue to work even after it is discontinued.
>
> Linkadge

Reboxetine (Edronax) did continue to "work" for me after I quit it, and till this day. I'm speaking of the depersonalisation (my main symptom is emotional detachment/blunting). It's a dissociative disorder.

I don't know about reboxetine, but atomoxetine is a kappa opioid receptor antagonist, and that is a receptor at which agonism has been found to induce depersonalisation in clinicial trials of (selective) agonists.

This is all I can find about it:
http://www.addforums.com/forums/showthread.php?t=56390

-undopaminergic

 

Re: Norepinehprine D4 receptor » undopaminergic

Posted by linkadge on June 1, 2020, at 5:29:40

In reply to Re: Norepinehprine D4 receptor, posted by undopaminergic on June 1, 2020, at 3:14:20

>atomoxetine is a kappa opioid receptor antagonist

Clarification - I believe it is an **agonist at the kappa receptor. Kappa agonism can cause dysphoria, which my be why atomoxetine failed as an antidepressant. Kappa antagonists (mirtazapine is a weak antagonist) have antidepressant properties. Dynorphin (a kappa agonist) is increased by stress and may be related to stress induced depression.

You're right that kappa agonists can produce depersonalization (akin to the drug salvorin-a in salvia). I actually liked salvia. There is some evidence that kappa agonists have anticonvulsant and anti-addictive properties.

Linkadge

 

Re: Norepinehprine D4 receptor

Posted by undopaminergic on June 1, 2020, at 6:37:28

In reply to Re: Norepinehprine D4 receptor » undopaminergic, posted by linkadge on June 1, 2020, at 5:29:40

> >atomoxetine is a kappa opioid receptor antagonist
>
> Clarification - I believe it is an **agonist at the kappa receptor.

Right. That is what I meant. Good catch!

> Kappa agonism can cause dysphoria, which my be why atomoxetine failed as an antidepressant. Kappa antagonists (mirtazapine is a weak antagonist) have antidepressant properties.
>

The most potent clinically available kappa antagonist is buprenorphine, and it does have antidepressant properties, but it is also a partial mu agonist.

I read that kappa antagonism increases dopamine release in the prefrontal cortex.

> Dynorphin (a kappa agonist) is increased by stress and may be related to stress induced depression.
>

I also read it downregulates dopamine D2-receptors

> You're right that kappa agonists can produce depersonalization (akin to the drug salvorin-a in salvia). I actually liked salvia.
>

Did you enjoy it more at peak, or was it the "afterglow"?

Myself, I couldn't get any effect at all.

> There is some evidence that kappa agonists have anticonvulsant and anti-addictive properties.
>

They do reduce cocaine self-administration in rats. However, kappa *antagonists* reduce it even more! My hypothesis is that the agonists reduce drug reward (perhaps via downregulation of dopamine D2), and antagonists counteract drug tolerance (thus lower doses are needed).

-undopaminergic

 

Re: Norepinehprine D4 receptor » undopaminergic

Posted by linkadge on June 1, 2020, at 10:56:31

In reply to Re: Norepinehprine D4 receptor, posted by undopaminergic on June 1, 2020, at 6:37:28

Hmm.

I remember reading somewhere that kappa agonists increased GDNF (a substances that apparently reduces additive like behaviors). I think that salvia has some agonist activity at d2 as well (have to look). Anyhow, I didn't mind salvia during the effect. I had some mild-moderate visual distortions and a loss of self-other boundaries. You could say that it induced some dysphoria, but it also felt like it had some mood stabilizing properties. There was a reduction in color perception (which rebounded after the effect wore off).

Anything that kills my ego helps my depression. (not my ego in the 'personality' sense, but my ego in the sense of hyperawareness of my own consciousness and mortality...how everything must be analyzed in a self-referential way). I like things that let me fade into the woodwork feeling part of something bigger without having to be bigger myself).

I suppose that antipsychotics can kill the ego as well, but I found they just induced feelings of worthlessness --- rather than self disappearance.

When I am suicidal its just that I want to stop feeling my consciousness. I want to be dead (in a sense) yet still be alive if that makes any sense. I crave drugs that make me feel disconnected yet still alive. Alive enough to live but not so alive to incessantly ruminate about my first world problems.


Linkadge


 

Re: Norepinehprine D4 receptor » linkadge

Posted by undopaminergic on June 2, 2020, at 2:45:32

In reply to Re: Norepinehprine D4 receptor » undopaminergic, posted by linkadge on June 1, 2020, at 10:56:31

> Hmm.
>
> I remember reading somewhere that kappa agonists increased GDNF (a substances that apparently reduces additive like behaviors). I think that salvia has some agonist activity at d2 as well (have to look). Anyhow, I didn't mind salvia during the effect. I had some mild-moderate visual distortions and a loss of self-other boundaries. You could say that it induced some dysphoria, but it also felt like it had some mood stabilizing properties.
>

Salvia has quite a short duration of action, as far as I can recall, so how did you come up with the hypothesis that it may be mood-stabilising?

> There was a reduction in color perception (which rebounded after the effect wore off).
>

I feel I have a reduction of colour perception all the time, and pramipexole temporarily restored it to normal.

> Anything that kills my ego helps my depression. (not my ego in the 'personality' sense, but my ego in the sense of hyperawareness of my own consciousness and mortality...how everything must be analyzed in a self-referential way). I like things that let me fade into the woodwork feeling part of something bigger without having to be bigger myself).
>

I suggest you look into Buddhist meditation. It is big on the idea of overcoming what they call "duality" (the duality of self and other).

> I suppose that antipsychotics can kill the ego as well, but I found they just induced feelings of worthlessness --- rather than self disappearance.
>

I have never experienced any loss of ego with antipsychotics, but I feel they may stimulate objectivity in thinking.

> When I am suicidal its just that I want to stop feeling my consciousness. I want to be dead (in a sense) yet still be alive if that makes any sense. I crave drugs that make me feel disconnected yet still alive. Alive enough to live but not so alive to incessantly ruminate about my first world problems.
>

Kappa agonists can make you feel disconnected, or detached. Or at least depersonalisation can, like you are an observer of life rather than a participant. This can be nice temporarily for coping.

Based on my own experience, I would suggest that stimulants can get rid of suicidal ideation, but you already tried that. Based on what I've read, lithium is also anti-suicidal.

-undopaminergic


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