• Neuroscience & Pharmacology Discussion Welcome Guest
    Posting Rules Bluelight Rules
    Recent Journal Articles Chemistry Mega-Thread
    FREE Chemistry Databases! Self-Education Guide

  • N&PD Moderators: Skorpio

Bupropion above 300 mg, counteract activation and induce fatigue - mechanism?

JohnBoy2000

JohnBoy2000

Bluelighter
Joined
May 11, 2016
Messages
2,650
Well - perhaps a difficult question to answer given that bupropions mechanism of action is not well known or understood.

Well, firstly to clarify - this has been reported anecdotally on several websites.

I found 300 mg to be activating and was seeing an increase in efficacy through a month long period.
At the end of one month, I assume it would be at full efficacy, and given that I was not experiencing full remission, I bumped it to 450.

Since then, it appears I have been experiencing more fatigue than when at 300 mg.
Prolonged fatigue.

I'm curious as to how the higher dose would result in fatigue, given that it's normally an activating drug.
Effects noradrenaline and dopamine - euphoric agents - unlike an excess of serotonin that could result in tiredness, I understand these would result in greater activation, right?

So again - why the higher level of tiredness at the higher dose?
 
It could be the dopamine reuptake properties or nicotinic acetylcholine receptor antagonism kicking in. I think there was question about whether or not bupropion appreciably affected dopamine at some dosages, or they found that an increase in dopamine happened with a certain route of administration which hints to me that you just have to push the dose to see dopaminergic effects (as I understand it, Ritalin is not necessarily a very wiring drug for some with ADHD for example).
 
Maybe you have adhd? I have adhd and I take much stronger ndris and at the peak effects im the least active and I actually feel the calmest and even kinda drowsy not like mentally drowsy but like body tired like I dont feel kike moving alot. To be more specific when I take my ndris they cause me to get hyper for the first few hours then progressively more calm and still.

I take modafinil and adderall.
 
Hmm - since when does dopamine induce fatigue?
I was under the impression that it was one of the "reward feeling" neurochemicals, euphoric, and would thus incite energy.
No?

And I don't have ADHD - lol.

You mean to tell me modafinil and adderall are NDRI's?
 
Well modafinil is also probably affecting histamine and adderall is a releasing agent, and bupropion is suspected to be a releasing agent (reverses transporter causing efflux of neurotransmitters) but I don't know if that effect is relevant.

But yeah, dopamine receptors are most often coupled to inhibitory pathways, that is when the dopamine receptor is bound by an agonist, it inhibits the cell it's located on. So depending on what's going on with the circuitry dopamine could have any number of effects. For example, if it was binding to a dopamine receptor on an inhibitory GABA neuron, then it would inhibit that inhibitory neuron and activity downstream would increase.

And also, if there's no hyperactivity then I suppose some ADD is still a possibility (just throwing it out there).
 
Elucidate me on what you mean by, further effects "downstream"??

Does that mean, not at the neuron itself?
Or what...
 
Right, so if you inhibit a pre synaptic inhibitory interneuron that normally releases GABA, then the post synaptic neuron's excitability is going to increase because the pre synaptic GABA interneuron is not releasing GABA that's normally binding post synaptically and reducing the chance an action potential will arise
 
======(presynaptic neuron) synapse (post synaptic neuron) ======

Receptors exsist on both sides for example tenex is a blood pressure medication but can also alter focus in adhv because

Low dose bind to the presynaptic receptors at alpha adrenic receptors causing paradoxical increase in norepinephrine in the frontaal brain

High doses bind to the post synaptic receptor causing vasodialation the opposite of epinephrine
 
Modafinil is still a bit of a mysetery. It's a DRI, but weak enough to minimize abuse. It has a decent efficacy profile as a D2 partial agonist. I believe it acts as an orexin antagonist.

Amp has been around for about 80 years. It's a NDRA, NDRI, reverse-transport facilitator, monoamine oxidase inhibitor at MAO-A (apparent at higher doses), it collapses the PH gradient while in vesicles, it increases the rate of certain natural chain-reactions in the brain (don't know too much about this one).

TBPH modafinil has a more safe and strong record as a nootropic.

But both of those are not antidepressants. They're both technically stimulants, and can both be abused and create addiction.

Bupropion is a mystery of sorts.
 
D2 receptor agonism is modafinils mode of stimulation??

How is that a D2 agonist like pramipexole made me drowsy as, in that case?


Whether pre or post synaptic action - I fail to see how the reference "downstream" applies.
In the sense that it is a post synaptic action or implication, as oppose to pre-synaptic, that yields the effect - is that what "downstream" means?
I had heard the word "protein binding" being thrown around in tandem with "downstream" - perhaps the two are co-dependent?

Low dose bind to the presynaptic receptors at alpha adrenic receptors causing paradoxical increase in norepinephrine in the frontaal brain

High doses bind to the post synaptic receptor causing vasodialation the opposite of epinephrine
Click to expand...


Is this in reference to bupropions mechanism of action??

Are you suggesting that higher doses, vasodialation (assuming this is pharmacodynamic fact - just the first time I've heard it, but am very much in the early learning stages), results in a weaker increase of epinephrine, than a lower dose?
 
Norepinephrine is activating.

Serotonin - not so much.

But as regards dopamine - I'm still in the dark.
Is it considered stimulating or no?
Depends on the subtype?
 
As far as I understand it, dopamine induces somnolence rather than fatigue. But I see can see how it would be hard to extrapolate one from the other.
 
JohnBoy2000 said:
Norepinephrine is activating.

Serotonin - not so much.

But as regards dopamine - I'm still in the dark.
Is it considered stimulating or no?
Depends on the subtype?
Click to expand...

Dopamine is considered neuromodulatory, as in it wouldn't be the best to generalize it as pro excitatory or pro inhibitory, although individual dopamine receptors are often coupled to inhibitory pathways - that is to say that when an agonist binds to a dopamine receptor, it will lead to a decrease in the likeliness that the neuron the receptor is located on will fire and release neurotransmitters downstream at its axon, which would be post-synaptically but if you were to take a step back this would technically be presynaptically at the next synapse. Position in the circuit and what it's doing functionally is what's important.

The other thing is that response to neurotransmitters is not linear, that is to say that flooding the brain with dopamine with a dopamine releasing agent is probably going to be very different than mildly increasing dopamine with a dopamine reuptake inhibitor.
 
Totally off topic sorry I was just trying to describe how pre and post synaptic receptors work idk what that has to do here I Just Saw Someone Mention It That Was An Easy Example With tenex
 
Bupropion itself is a legit NDRI in vitro, but if taken orally almost all of it gets metabolized before reaching systemic circulation, producing metabolites that are NRI and lack any noticable effects on dopamine.

But if Bupropion is administered IV/IM/nasal/rectal the "first pass effect" is bypassed, allowing Bupropion to reach systemic circulation unchanged and deliver its NDRI activities to the subject.
 
Will miss Tram :( said:
Bupropion itself is a legit NDRI in vitro, but if taken orally almost all of it gets metabolized before reaching systemic circulation, producing metabolites that are NRI and lack any noticable effects on dopamine.

But if Bupropion is administered IV/IM/nasal/rectal the "first pass effect" is bypassed, allowing Bupropion to reach systemic circulation unchanged and deliver its NDRI activities to the subject.
Click to expand...

Well
Well some claims go as such but, scans show that it does increase dopamine levels in the brain, PFC or such - and I understand that can be as a product of dopamine "hitching a ride" to the noradrenergic inhibition...... or can it?

If that were the case, it acts as purely a NRI, with no dopamine activity - so, similar to the novel reboxetine.

Even though their ultimate mechanisms of action are different.
Reboxetine having affinity for NAT, and buproprions being unknown supposedly.... according to its binding affinities.

Then there is the claim that bupropion DOES implicate dopamine when it reaches about 450mg dose.
Which I have read anecdotally - but no mechanism as to why that's the case has been explained, to me at least.
 
There really isn't much dopamine transporter expression in the PFC, therein dopamine reuptake is handled by the NET. So inhibiting the NET results in an increase in dopamine in the PFC.

I think a possibility is that at 450mg oral enough bupropion might make it to the brain unmetabolized that it could start to exert relevant releasing agent effects.
 
Simplified norepinephrine is related to dopamine so effecting one will tend to have so effect on the other. However, unlike amphetamine and cocaine wellbutrin is many fold more selective for norepinephrine
 
Sometimes ADHD patients experience a feeling of fatigue when on stimulants. If youre looking for something physically activating, maybe desipramine might be worth trying?
 
cr33py said:
Sometimes ADHD patients experience a feeling of fatigue when on stimulants. If youre looking for something physically activating, maybe desipramine might be worth trying?
Click to expand...


Good suggestion, but it's totally unavailable in the UK.


It can't even be sourced, which means it's n/a in europe in general.


What country does prescribe it?
The US?
 
You must log in or register to reply here.
Top