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Implications for Cholinergic Effects of Cortical Norepinephrine Activity

atomoxetine cholinergic reboxetine. sct add adhd cdd alpha1 norepinephrine

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#1 devinthayer

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Posted 30 June 2016 - 10:54 PM


 
Procholinergic and memory enhancing properties of the selective norepinephrine uptake inhibitor atomoxetine.

 

...atomoxetine (0.3-3 mg/kg, i.p.),--increases in vivo extracellular levels of ACh in cortical but not subcortical brain regions. The marked increase of cortical ACh induced by atomoxetine was dependent upon norepinephrine alpha-1 and/or dopamine D1 receptor activation. We observed similar increases in cortical and hippocampal ACh release with methylphenidate (1 and 3 mg/kg, i.p.)--currently the most commonly prescribed medication for the treatment of ADHD--and with the norepinephrine uptake inhibitor reboxetine (3-30 mg/kg, i.p.). Since drugs that increase cholinergic neurotransmission are used in the treatment of cognitive dysfunction and dementias, we also investigated the effects of atomoxetine on memory tasks. We showed that, consistent with its cortical procholinergic and catecholamine-enhancing profile, atomoxetine (1-3 mg/kg, p.o.) significantly ameliorated performance in the object recognition test and the radial arm-maze test.

 

 

 

I am a big believer that Sluggish Cognitive Temp (SCT) aka Concentration Deficit Disorder (CCD) aka "The Daydreaming Disorder" is characterized by a lack of cortical alpha1 adrenergic agonism in the pre-frontal cortex.  It's a little backwards of me to say this, but atomoxetine is the only known drug to show improvement in SCT/CCD.  It's my theory to say that this is because those who daydream for no reason (and who just get jealous of everyone else's mental capacity to do important stuff in the right order without breaking a sweat) have low alpha1 receptor activity in the PFC.

 

To put this theory to test, if you have SCT/CCD, you can take some oxymetazoline up the nose, which has a pretty good selection of alpha1 over alpha 2 receptors.  If it enhances memory and attention span and reduces daydreaming, I may be right.

 

Works for me, but the rebound sucks.  Gives me a stuffy nose for a solid three days, so I switch to pseudophedrine for those three days.  I also just feel weird shooting up nasal spray when I'm not sick.  I have it in my car, in my desk, and in my nightstand for when I need to concentrate but suck at life.  Also interesting is that alpha1 receptor activity increases estrogen receptor density... or at least antagonism does the opposite (sorry, lost my source, have to post it later), so it's safe to say it works the other way around.  It's another reason why'd I'd opt to go with a selective norepinephrine reuptake inhibitor vs. a straight alpha1 agonist.  Also another reason why I use oxymetazoline sparingly.

 

I just thought it was interesting that norepinephrine and acetylcholine activity were pals through D1 and Alpha1.  D1 has a U shaped curve for (spatial) memory performance.  There are more than one study out there that prove that, so I'll just go on to say that a non-U-shaped curve on memory of increased NE activity in the PFC probably has to do with the Alpha1 receptor.  Also consider the higher affinity that norepinephrine has for alpha1 vs. D1 and because of that, alpha1 receptor activitation is a lot more likely from atomoxetine (whose affinity for NET vs. DAT is like 100-200x higher).

 

So yeah, I get pretty pumped when I realize that I don't need to be taking a whole lot of cholinergic supplements once I've got the alpha1 activity down.  Still some, obviously, since ACh is necessary in the subcortical regions like the hippocampus for making good mental maps and stuff.



#2 gamesguru

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Posted 01 July 2016 - 01:02 AM

is sudafed a1 selective? probably a similar runny nose rebound, however. and what about something up- or downstream (just ACh or DA?) of the adrenoreceptors?



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#3 devinthayer

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Posted 01 July 2016 - 02:18 AM

Sudafed is mostly alpha selective, but it also affects betas a little as well as releasing norepinephrine. Since it's all around adrenergic activation takes place, I don't really get a crash or rebound.


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#4 Finn

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Posted 01 July 2016 - 05:06 AM

Methylphenidate and Atomoxetine Enhance Prefrontal Function Through α2-Adrenergic and Dopamine D1 Receptors 

 
The stimulants, methylphenidate, Concerta and amphetamine, lisdexamphetamine (Vyvanse, Elvanse), and the nonstimulant, atomoxetine, increase norephinedrine (NE) and dopamine (DA) transmission in the prefrontal cortex whereas guanfacine and clonidine mimic NE actions at α2A receptors
 
So atomoxetine may also be beneficial in it's  α2A  actions when it comes to cognitive performance.

 It's another reason why'd I'd opt to go with a selective norepinephrine reuptake inhibitor vs. a straight alpha1 agonist. 
 

 

 

Did you try to combine either α2A  agonist or beta blockers with atomoxetine (Strattera), or any other NRI?  
 
 α2A  agonist (guanfacine, clonidine) and beta blockers often cause weight gain as side effect, so if you quit atomoxetine because of excessive weight loss, those could help to combat it, and  α2A  agonist  could also have beneficial effects on ADHD symptoms. Some people on atomoxetine who get enlarged prostate issues as side effect also use α1 blockers like Tamsulosin, but if  α1 agonist gives you beneficial effects then maybe not use that, also it doesn't seem to list weight gain as side effect.  https://en.wikipedia...wiki/Tamsulosin
 
But if you haven't tried it yet, adding either beta blocker or α2A  agonist could help with atomoxetine or other NRI could help with excessive weight loss.

Edited by Finn, 01 July 2016 - 05:18 AM.


#5 devinthayer

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Posted 01 July 2016 - 11:15 AM

That's so funny. My landlord and I were just talking about enlarged prostate and stuff. Alpha1 antagonists just help you pee better by relaxing the muscles. If all of its activity is presynaptic, then that drug would be cool. I don't know if alpha1 antagonism stops enlarged prostate... I think you need a DHT blocker for that.

Alpha2a agonism never worked for me. I've tried guanfacine, but it just made things worse. Made me sleepy and crash harder from the stimulants. If I just took one to go to sleep that lasted 24 hours, then that combined with a time released stimulant might work... But only because I was getting better sleep and managing the hypertension better.


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#6 gamesguru

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Posted 01 July 2016 - 01:29 PM

lots of natural a1 antagonists, a few for a2. i think the dose has a lot to do with preference for presynaptic sites, at larger doses the postsynaptic also gets saturated. it cant all come down to chemical structure when the two receptors are so similar. it could also be something special to alpha 2 receptors, like they are more densely populated on the preterminal:

... presynaptic effects of phenylephrine on glutamate and GABA release were blocked by specific α1 adrenergic receptor antagonists.

 

Maybe control inflammation as one step?

Our data show that endotoxemia [and cytokins] causes a systemic down-regulation of alpha1-receptors on the level of gene expression and suggest that this effect is likely mediated by proinflammatory cytokines in a synergistic but nitric oxide-independent fashion. We propose that this down-regulation of alpha1-adrenergic receptors contributes to the attenuated blood pressure response to norepinephrine and, therefore, to septic circulatory failure in patients.

 

Thyroid function too?

In the hypothyroid state, the density of alpha1 adreno-receptors is increased but the density of beta adreno-receptors is reduced.[23] This results in increased smooth muscle contraction causing vasoconstriction.

 

Only verified in blood vessels, but it may decrease overall with age:

Human vascular alpha(1)AR subtype distribution differs from animal models, varies with vessel bed, correlates with contraction in mammary artery, and is modulated by aging. These findings provide potential novel targets for therapeutic intervention in many clinical settings.







Also tagged with one or more of these keywords: atomoxetine, cholinergic, reboxetine., sct, add, adhd, cdd, alpha1, norepinephrine

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