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Alpha adrenergic AGONISTS?

JohnBoy2000

JohnBoy2000

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May 11, 2016
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I was browsing some websites, and some info on treatment of chronic fatigue, was the use of an alpha adrenergic agonist - Naphazoline - found, in eye drops.

Would that not act to reduce the overall level of noradrenaline - being the opposite of an alpha antagonist like remeron?
So - for someone who BENEFITS from alpha antagoism, taking an AGONIST, could actually have the reverese effect and worsen the symptom of fatigue, no?

That initial durg trial was hypothesized by Dr Jay Goldstein..... some shrink who had an interest in chronic fatigue syndrome.
 
It could just be an agonist at alpha 1 heteroreceptors rather than, like clonidine, an agonist at a2 autoreceptors

Alpha 1 antagonism tends to decrease serotonin and cause sedation.
 
Picture ten bowls. Five bowls on the left side five bowls on the right.

Only the five bowls on the right are active
The five on the left have to be full before anything can fill the bowls on the right

You have three options green marbles (alpha adrenic 1 agonists) , red marbles (alpha adrenic 1 antagonists like mitrazapine), and black marbles (noradrenaline)

Possibility one 0 green 0 red 7 black
Left side all black
Right side two black

Net effect +2

Possibility 2 3 green 0 red 7 black
Left side 3 green two black
Right side 5 black

Net effect + 5

Possibility 3 0 green 3 red 7 black
Left side 3 red 2 black
Right side 5. Black

Net effect +5
 
d1nach said:
Picture ten bowls. Five bowls on the left side five bowls on the right.

Only the five bowls on the right are active
The five on the left have to be full before anything can fill the bowls on the right

You have three options green marbles (alpha adrenic 1 agonists) , red marbles (alpha adrenic 1 antagonists like mitrazapine), and black marbles (noradrenaline)

Possibility one 0 green 0 red 7 black
Left side all black
Right side two black

Net effect +2

Possibility 2 3 green 0 red 7 black
Left side 3 green two black
Right side 5 black

Net effect + 5

Possibility 3 0 green 3 red 7 black
Left side 3 red 2 black
Right side 5. Black

Net effect +5
Click to expand...

A new pen-&-paper table-top game, right from the late '70s before computers. Call it "Drugged Dendrites and Dragons chased"
 
Nagelfar said:
A new pen-&-paper table-top game, right from the late '70s before computers. Call it "Drugged Dendrites and Dragons chased"
Click to expand...

Yeah in the first situation - only 7 balls are used.

Are what are the bowls on left and right mean to represent?
Why are the numbers chosen as such - a very ambivalent example if you don't know the particulars (which I don't).

i.e. - sense - it doesn't make.
 
How both alpha adrenic agonism and antagonism can increase the amount of noradrenaline on the post synaptic alpha adrenic receptors despite having oppositing actions because by occupying the presynaptic receptors it increases the noradrenaline free to bind to the post synaptic ones
 
I think there is actually a name for that concept (ligand depletion?) but I don't think its thought to play a significant role because there are usually hundreds upon hundreds of ligands for every receptor in question. I'm also not aware of a1 being expressed much pre-synaptically, but in that case if it bound there antagonistically then it would just function as an autoreceptor antagonist so you wouldn't necessarily need a competitive "NE can't bind presynaptically because the ligand is bound there so it decides to bind postsynaptically" kind of explanation for why presynaptic a1 blockade (if there is such a thing) increases signaling at postsynaptic heteroceptors.
 
Good point cotcha I looked back on trazadone and Seroquel and it just says adrenic receptor autoreceptors increasing noradrenaline signaling. So this may just apply to the alpha adrenic type 2
 
Okay so - the use of these eye drops - as a potential indicator that NA is potentially the NT implicated in the chronic fatigue of a patient - is valid, you're basically saying, regardless of being an agonist or blocker.

Alpha 1 receptors - do they have opposing effect depending on which neuron their located?
On 5HT neurons, I know when blocked, they inhibit the release of 5HT from its neuron - cause that's the principle on which Mianserin works as being solely an NE agent - versus Mirtazapine being both 5ht and NE, as the latter has not alpha1 blocking properties.

But on NE neurons - I can't remember whether they incite or inhibit NE release - but you guys are saying, either way, the potentiate the NE effect as it's increasing the availability of NE NTs to bind post synaptically, right?
But, if it were to inhibit the release of NE, the agonist bonding to the the a-receptor, despite the aforementioned potentiation - it wouldn't be as potent as an antagonist, which would increase post synaptic availablilty, AS WELL as raising the NT levels in the synapse - no?
 
This Dr Goldstein claims that the eye drops can incite an energy increase within minutes..... relieving CFS.

Increasing NT levels in the synapse, thus - desensitizing post synaptic receptors...?
Wouldn't that still take weeks, similar to AD mechanism of action - regarding the downstream modication and signal transduction, ultimate relay of the post synaptic neuron genome (or brain of that neuron is what I mean), to relay the information to downregulate the hypersensitive receptors?

How does this "immediate energy increase" work?
 
Who is doctor Goldstein and what eye drops? I've never heard of anything remotely close to this. R u putting them on your eye or eating them
 
d1nach said:
Who is doctor Goldstein and what eye drops? I've never heard of anything remotely close to this. R u putting them on your eye or eating them
Click to expand...

They're what I was referring to with this thread.

Nephazoline 0.1% eyedrops - alpha 1 agonist.

You put them in your eye.

Goldstein is a shrink that specialized in CFS.
 
"NE makes depressed people feel better, so surely they have a deficit of NE!"

Anyways, a1 couples with a G-protein called Gq that mediates downstream effects via PLC and IP3. This is going to have different effects depending on where/when a1 is being activated in different cells, and the response to NE across the 3 major classes of NE receptors (a1, a2 and b2) is known to be non-linear (https://www.ncbi.nlm.nih.gov/pubmed/19279145/)

"but you guys are saying, either way, the potentiate the NE effect as it's increasing the availability of NE NTs to bind post synaptically, right?"
I would delete this phenomenon from your brain - I think there are probably hundreds of NTs per receptor.

"Increasing NT levels in the synapse, thus - desensitizing post synaptic receptors...?
Wouldn't that still take weeks, similar to AD mechanism of action - regarding the downstream modication and signal transduction, ultimate relay of the post synaptic neuron genome (or brain of that neuron is what I mean), to relay the information to downregulate the hypersensitive receptors?

How does this "immediate energy increase" work?"

With SSRIs it is thought that it takes a few week for pre-synaptic (somatodendritic) autoreceptors like 5-HT1A to desensitize, while the post-synaptic 5-HT1A (heteroceptor) sensitize with time and are critical to SSRI response. A theory of tricyclic AD response is essentially that NE magnifies the response to 5-HT, essentially that 5-HT is still doing the heavy lifting. NE also increases the activity of 5-HT cells.

"Tricyclic antidepressants (TCAs) have been hypothesized to act via a distinct mechanism to that of SSRIs, enhancing tonic serotonergic transmission by facilitating the activation of G proteins by the postsynaptic 5-HT1A receptor, thereby increasing the sensitivity of the post-synaptic receptor rather than desensitizing the 5-HT1A somatodendritic autoreceptor (Gravel and de Montigny 1987) (Chaput et al 1991) (Blier and Bouchard 1994) (Rossi et al 2006).
The increased sensitivity of post-synaptic 5-HT1A receptors has also been shown to occur in limbic structures such as the hippocampus following repeated administration of electroconvulsive shock (ECS) (Hayakawa et al 1994) (Ishihara et al 1999) or the selective norepinephrine reuptake inhibitor reboxetine (Szabo and Blier 2001)." (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2736801/)

However I'm not sure what exactly is mediating the acute mood benefits of NE. I wouldn't expect them to hold up over time however, but the 5-HT1A response should kick in at some point, as well as 5-HT's effect on neuroinflammation. In some cases in the rat brain, NE increases GABA release via a1a.

A1b is very important in mediating a lot of the effects of psychostimulants and opioids, it controls dopamine release and behavioral sensitization (both dopamine release and behavioral sensitization seen with addictive drugs can be blocked with a a1b antagonist).

But I would be very careful with the Dr. Goldstein type people, everybody has their own unsubstantiated theories. Knowing that NE helps depressed people feel better is helpful for figuring out the causality of depression but we shouldn't stop at "Increasing NE helps depressed people get their energy back so maybe depressed people have a deficit of NE" - maybe they have normal NE levels but their network isn't responding normally to NE because of issues with the neurons communicating with each other as a network.
 
I would add that it is probably not NE that is making people feel better, but rather it seems to be that altering NE transmission chronically changes how other downstream targets function.
 
Serotonin, do you think that a selective NRI has any short term or long term utility in treating MDD? It seems to me like it may only be an immediate suicidality type tool, and that a selective NRI would probably be approved for MDD if NRIs had long term efficacy... At least I'm not aware of an NRI approved for MDD by the FDA.
 
Reboxetine. Hoed u fi d this guy i cant find him on google. So hes suggesting u take eye drops for depression? By shrink is he a doctor i dont think hes legally allowed to recommend unapproved drugs if hes a md
 
And what is cfs??? Im too intoxicated to understand what cotcha said but i honestly have never heard anything even close to what goldstein is saying. He could be right i just dont know
 
CFS is chronic fatigue syndrome which seems to be a "we don't know whats wrong with you" diagnosis in some cases. I'm not too educated on that matter. I'm not saying its not real but it does seem like a weird thing, its associated with fibromyalgia. Which, again, for some people is a very real disorder with biomarkers and such, abnormalities in inflammatory markers and sleep architecture even.

Concerning Reboxetine, to quote wiki "It is approved for use in many countries worldwide, but has not been approved for use in the United States. Although its efficacy as an antidepressant has been challenged in multiple published reports, its popularity has continued to increase.[4]"

I just get the feeling that selective NRIs mainly offer acute symptomatic relief and that they poop out at some point. I believe I've seen a study showing benefit up to their final follow up 11 weeks, so there is at least that. I suppose a change in mental activity could confer long term benefits. Decreased rumination for a couple weeks surely is going to offer some benefit that persists.
 
Hmm I could have sworn when I was in outpatients a few girls where on it because they where talking about it reducing their appetite. I don't understand the off label use for panic disorder either wouldn't it just make them more anxious
 
d1nach said:
Hmm I could have sworn when I was in outpatients a few girls where on it because they where talking about it reducing their appetite. I don't understand the off label use for panic disorder either wouldn't it just make them more anxious
Click to expand...

It seems a lot of NRI's have that appetite reducing property.
Bupropion, lofepramine - which I'm on.

But - did you get feedback, albeit annecdotal - that reboxetine was an effective medication?

In some small trials it seems that it works where SSRI's don't.
On larger scale trials, it seems to fall short of SSRI's, but wouldn't that be because for a lot/most people, serotonin is the implicated NT, and NE is not - where reboxetine is a selective NRI - the first one approved for depression.

In other words - the clinical trial data may be lying to us.
 
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