Neurochemicals most intimately involved with cognitive and executive function?

[JohnBoy2000]

Serotonin does not seem to play any role in this capacity.

Due to the improvement in cognitive function in parkinsons sufferers when treated with dopamine agents, that would infer that dopamine is involved in cognitive functioning.

It seems to be well known that noradrenaline is "intimately involved" in executive and cognitive function.

What else is there?

Opioid receptors?

mACH receptors?
I doubt it, seems as they seem to impair function with blurred vision etc.

Histamine receptors - induce somnolance.

That being said, I don't actually know so, I'm asking.

And what AD's would act most strongly on dopamine as a means to improve cognitive function?
There doesn't seem to be any/many drugs that act exclusively on this, apart from the parkinsons agents, and I don't think they're used to treat depression, even off license.

 

[sekio]

There isn't a single NT that you can point to and say "that is responsible for executive function", to function effectively there must be multiple signalling systems working in concert. Disrupt any one of them and you will alter executive function in some manner.

Dopamine and norepinephrine are certainly major players but realistically, increasing their levels doesn't necessarily increase executive functioning - NE generally tends to cause fight-or-flight type responses and excessive DA disrupts reward circuitry and causes motor tics. I can assure you that a strong dopamine blocking drug like haloperidol is most effective at limiting cognitive functions. And on the other hand, norepinephrine release blockers like clonidine are used as strong sedatives that cause sleepiness and sometimes even fainting spells.

Likewise, no one neurotransmitter is responsible for positive mood. I suspect that just like executive function, happiness comes from having all the neurotransmitters working together - not just "more dopamine" or "more serotonin".

Serotonin plays plenty of a role in executive function, BTW. (really, all of the monoamines* do) Take ~250 ug of LSD (serotonin 2A receptor agonist) in a dark room and tell me that your executive functioning isn't affected. Likewise, blockade or stimulation of certain serotonin receptors is an important part of many antipsychotics and some anti-depressants/anti-anxiety agents.

* serotonin, norepinephrine, dopamine, adrenaline, histamine, acetylcholine, phenethylamine, tyramine, tryptamine, anandamide, virodhamine and so on are all technically monaomines involved to some extent or another in our psyche. And that's only monoamines I can think of off the top of my head, not counting other stuff like the peptides.

 

[Seppi]

Dopamine and norepinephrine are certainly major players but realistically, increasing their levels doesn't necessarily increase executive functioning - NE generally tends to cause fight-or-flight type responses and excessive DA disrupts reward circuitry and causes motor tics. I can assure you that a strong dopamine blocking drug like haloperidol is most effective at limiting cognitive functions. And on the other hand, norepinephrine release blockers like clonidine are used as strong sedatives that cause sleepiness and sometimes even fainting spells.

Modestly increased DA/NE levels (via releasing agents/reuptake inhibitors) in the PFC (VTA-PFC + LC-PFC pathways) in the average individual induces beneficial effects on cognitive control via alpha-2 adrenoceptors and DRD1 signaling. Link + related meta-analysis link

DA could potentially have an effect on executive function via signaling in the dorsal striatum since that region is involved in "inhibitory control", a core executive function.

@OP: I haven't read anything about other neurochemicals having an effect on cognitive control when their basal levels are altered.

 

[aced126]

Also, activation of b-adrenoreceptors by norepinephrine in the amygdala enhances the encoding of emotion-related or "flashbulb" memories.

 

[Cotcha Yankinov]

Parkinson's patients could be experiencing improvement in cognition with agents that boost dopamine almost entirely because their dopamine producing cells have died off - that doesn't necessarily mean that boosting dopamine in a normal person will have a linear effect on cognition. At some point the increase in dopamine will be counterproductive, essentially a decrease in the signal to noise ratio.

Glutamate, AMPA/NMDA especially, is pretty important for cognition though.

 

[JohnBoy2000]

https://clinicaltrials.gov/ct2/show/NCT00125957?term=bupropion&rslt=With&rank=5

This study outlines how serotonin does not improve executive function, where noradrenaline does.

Glutamate, NMDA receptors - what medications would focus on them specifically?
I'm still a little hazy on this angonizing vs antagonizing.
I know one stimulates the transmitter above baseline function, the other relaxes it to baseline function.
But in terms of what incites a benefit?
Would agonism not be the useful effect?
Yet I read about how dopamine or adrenergic receptor antagonsim incites the drugs noradrenergic effect etc.
I gotta study this more - I just downloaded a couple of books but, until then, maybe you guys can fill me in on this area?

That and, how exactly is noradrenaline enhanced i.e. what receptor is responsible for it?
With mirtazipine by example, I see it has effect on a range of the 5-HT subreceptors, and the alpha adrenergic receptors (is this what's implicated in noradrenaline..... release?).

But what receptor is responsible for greater NET??
As I would assume the 5-HT receptors are responsible for SERT.

 

[AlphaMethylPhenyl]

Yeah, as others have said/implicated, the question is pretty broad and the answer largely dependent on a case-by-case basis. Like for example if someone has a phobia about giving speeches and takes a small dose of xanax before their speech, cognition could improve, but xanax on its own doesn't really

But, generally, frmo my understanding...

Dopamingeric stimulation in the prefrontal cortex (D1 agonsim), and D5
Nicotinic acetylcholline agonism (some subunits, including alpha7)
Glutamatergic substances, though those can be toxic and I don't know too much about them
Adenosine antagonism
For someone to stay focused and engaged, there must be a decent amount of mu opioid agonism/D2 agonism in the limbic, but too much and you also get a high, and too much more and cognition degrades (I think opiates are a decent direct example of this, but they're clearly not worth it)

NET is a transmembrane transporter/reuptake pump that sucks up NE when the brain tells it that too much is in the synapse. Norepinephrine is a catecholamine chemical, which basically means its stimulating. NE action can be enhanced in a number of ways. Autoreceptor antagonism, reuptake inhibition, agonism, reverse transport, Adenosine blockade.

More the other way around. SERT picks up extra serotonin to be metabolized/repackaged once in the presynaptic neuron.

Sedating neurotransmitters/hormones like melatonin/GABA/(most regions of the serotonin receptor) to help sleeping work to promote fresh thought during the day

 

[Seppi]

@OP: I haven't read anything about other neurochemicals having an effect on cognitive control when their basal levels are altered.

Following up on what Ho-Chi-Minh said, one could infer from the entry on nicotine in this link that acetylcholine is involved in attentional processes; I'd assume a modest increase in cerebral acetylcholine concentrations would improve at least some executive attentional processes based upon the effect of alpha-4 beta-2 receptor agonists, but I can't say for sure since acetylcholine would also agonize other acetylcholine receptors which might offset this effect.

 

[JohnBoy2000]

Okay, I suppose when I say executive function - I understand that can be interpreted broadly.
By example, if someone has their schizophrenic symptoms reduced by use of olanzapine - then perhaps there will be an increase in their functioning, despite the fact that olanzapine is a sedative.

Specific to depression however.

By example, there seems to be a hypothesis that in terms of alleviating depression whose nature is associated more so with, "sadness", ruminating, unhappiness, poor thought process - that type of thing.
In that instance, serotonergics are more effective.

For depression specifically associated with, cognitive impairment however - low energy, fatigue, insomnia, low appetite - where ruminating and "sadness", per se, are not involved so much, and oftentimes the patient can be motivated, goal orientated, driven etc.
In that instance, the hypothesis is that, that type of depression responds better to noradrenergics.
i.e. it alleviates cognitive impairment.
That is to say, it is better are restoring executive function.


I suppose my question was, in this instance, for depressive related cognitive impairment, are there any other neurochemicals specifically involved in the increase of executive function, the restoration of functionality - where depression/low mood, is the cause of the cognitive impairment?

As in, noradrenaline, from what I understand, is known to be an activating neurochemical.

Does, dopamine, fall into a similar category?
Opioid receptors?
mACH receptors?
Histamine receptors?
Alpha adrenergic receptors? (I'm still not clear as to how these are related, or not related, to noradrenergic transmission).

 

[Limpet_Chicken]

Histamine does seem to play an activating, focusing type role (bear in mind I GROSSLY oversimplify), in some respects at least. Doesn't modafinil act in part on histaminergic transmission? I've taken betahistine, a histamine H3 antagonist normally used to treat meniere's disease, a disorder of balance resulting from inner ear issues, don't have that. It helped with my difficulties, especially when combined with racetam/anticholinesterase combinations such as aniracetam, pramiracetam/piracetam and galantamine (best) or the not nearly as good huperzine-A (lacks the alpha7 nicotinic agonism as an additional nootropic effect and additionally its an antagonist at polyamine sensitive NMDARs. Not sure what significance that has at physiological doses of huperzine-A.

Cholinergic transmission is central in cognition, as are glutamate and GABA. There is a severe cholinergic hypofunction observed in alzheimer's and other dementias. And some of the best (limitedly effective in dementias) treatment we throw at it are cholinesterase inhibitors.

 

[Cotcha Yankinov]

I think boosting norepinephrine works well for what they call psychomotor retardation.

 

[Limpet_Chicken]

What is meant by psychomotor retardation. Familiar with retardation of reaction rates, catalytic activities (catalyst poisoning etc), and mental retardation (both from reading medical science of course, but some of his former girlfriends have been mentally retarded, no insult meant to those who did have MR however) but not familiar with 'psychomotor retardation. never come upon that term before.

Things like say, ataxia?

That would be good to fix, although noradrenergic activity increase is one thing I have to avoid like the plague. In fact I go about my days loaded up to from arse ring to eye teeth with clonidine and tizanidine. The former helps me no longer overload much and the tizanidine I need to block severe muscle spasticity that results from some localized nerve damage. The latter is otherwise horrendously painful. Although I daresay the mix of the two alpha2 adrenergic autoreceptor agonists really REALLY potentiates opiates. Just spent an entire DAY, since 8am, fast asleep on the sofa from a fraction of my typical painkiller dose, even after my chlormethiazole had worn off. 240mg oxy, plugged was all I had and it send me fast asleep. And very glad I am it did too because I hadn't slept in days before.

 

[JohnBoy2000]

Okay - allow me to simplify matters.

Cognitive dysfunction, relative to - poor concentration, low motivation, fatigue, malaise.

Nor-adrenaline, one would certainly consider being a key player, no?

 

[Cotcha Yankinov]

Psychomotor retardation is a term people tend to use in the context of major depression, when you don't have the energy/motivation to carry out some physically oriented task, "I can't go get the mail, it's so exhausting" sort of thing.

Johnny boy, norepinephrine and dopamine play big roles in combatting fatigue and increasing concentration (if only by dopamine increasing the activity of NMDA) but SSRIs can help with whatever because serotonin regulates a lot of neural activity and helps the brain cells (it's a good idea to look beyond just receptors). I think specifically more norepinephrine was found to help with psychomotor retardation and some depression symptoms and an NRI like Atomexetine has use in ADHD, but SSRIs/SNRIs are probably better agents for MDD long term.

 

[Limpet_Chicken]

Ah, so you meant aesthenia/neuraethenia?

Still, got to avoid adrenergic agents other than sympatholytics. Even things like mirtazepine in a fraction of a tablet dose made me feel so hideously awful I would have thrown myself out of a window if I could have done at the time to make it end. Thats not a reflection upon mental state alteration caused by it, I was efectively once forced onto it for sleep issues, and ended up flushing it down the toilet instead, it was a PURELY physical reaction, and it was..well there are few words that even come close to describing how utterly agonizing it was, even at a bit less than 2mg.

Piribedil I did manage to borderline tolerate at one time out of desperation to try and help restore some shattered mnemomic function, although I still had to mix it with increased doses of zanaflex (tizanidine) and clonidine

 

[serotonin2A]

Ah, so you meant aesthenia/neuraethenia.

Neuraethenia is not exactly the same thing. Psychomotor retardation is a symptom; neuraethania is (well, at least it used to be) a medical diagnosis. Because neuraethania is no longer considered to be a valid diagnosis, the terminology is no longer in common use.

 

[Limpet_Chicken]

The former the physical manifestation of a psychological (or, the physical manifestations of the psychological distillate of a physiochemical root cause of course) compared to a not necessarily psychologically involved, physical or directly physiochemical cause, potentially without the involvement of a depressive psychological response in the case of aesthenia)

Might be somewhat of an old fashioned dx. But at least as a descriptive term I can think of a couple of people who it fits pretty well. Such as one lady, this one, wonderful, gorgeously classically autistic, aloof, and absolutely beautiful, stunning, incredibly bright, special perfect girl, who has a pretty squirrely HPA axis along with diffuse white matter lesions and adrenal insufficiency, my...stalker, and former girlfriend (would get back with her in a heartbeat given a chance to)

Plus a girl I know who has Rett syndrome and similarly, hypothalamic-adrenal issues although I don't think pituitary issues (at least she hasn't mentioned having particular pituitary involvement).

(and lol, whilst the other one, the Rett's girl and I have never been an item....god DAAAAMMMNNNN............................................................wow!. Including the above ex gf I've only ever known once. MAYBE twice, anyone quite so stunning. Body to DIE for, and I mind that just sets me on fire. Although the aesthenia tendency seems to be shared in common between the two women, although much more strongly in my ex) I have a hunch that its got a lot to do with ACTH/glucocorticoid levels [and possibly CRF or CRF-binding protein of course, and potentially the likes of point mutations in either receptor genes, proopiomenalocortin genes and such]

 

[Cotcha Yankinov]

I was under the impression that MDD patients show elevated stress hormones. I don't know if that observation fits with a theory of low glucocorticoids causing psychomotor retardation (in depressives) although the opposite could be true I suppose, chronically high stress hormones leading to psychomotor retardation.

 

[Limpet_Chicken]

Well that was the interesting bit, these two, my ex (the autie one) and the searing hot stuff one with the body and brain that I'd love to eat for breakfast and dessert (the Rett's girl) are not, as far as I know MDD, the first of the two used to take an SSRI) but the girl with Rett's, I don't think she does, in fact I seem to recall something about her telling me SSRIs make her all squirrelly (and not in the good sense, shes squirrellier than a sacked and pillaged nut orchard in THAT sense [in the good way, and a waaaay beyond any use of the term 'cute' kind of level [yes, I know, its probably obvious...she's got me *SO* in love, lol. ok, I admit it, she does and I am, she drives me nuttier than every damn tree in the country]

And to the most of my awareness she isn't MDD either. But she can't produce corticosteroids, at the ACTH level. My ex, she has difficulty doing so and takes a supplemental corticosteroid dosage, (autie girl) but the Rett's lady, she'd be dead most likely without steroids, and if she gets into serious trouble, such as seizures, serious illness then she HAS to have them, and pretty certain she carries a steroid warning card. Its a miracle, a true, beautiful, sweet, wonderful miracle she is alive to this day, and one that I think of often and smile.

 

[Mracid]

I would litterally say that every single receptor in your brain is used in cognitive functionning. Your cortices are all functionning to calculate and send informations. Your thalamus is recieving and relaying the informations to either association cotex or brainstem or cerrebellum, which is what makes the information calculated and sent to become something you can percieve or a physical action. I would say that only Pyramidal tract isnt really a cognitive related action but then again you need to understand which muscle you want to move before moving it so thats a cognitive function.

Your prefrontal cortex is the one who recieve information to be organized and structured and sent back to the thalamus.

So basically; NT: DA, NE, SER, Melatonin, Histamine, Glu, GABA, Anandamide, ACh, Gly, Aspartate, D-serine, NO, CO, H2S, so every amino acid with activity at a neuroreceptor, Trace amines, Peptides, Purines, even neurohormones.
Then there are second messenger that translate the message into the neuron for it to change some of its qualities; mostly enzymes, proteins, fatty acids etc.
Then there are Voltage gated channels that recieve ions like Na+, K+, Ca++ etc.

Cognitive functions are made of systems of transmission of informations that interact with each other to create a pattern of action that you can recognize as a memory, an understanding or a thought. So basically I do not think that any neurotransmitter is left with a specific role, I think their role is entire related to where they are and with the amount of neurons in the brain I think there is at least one of each in every cortex even if its a low amount. The patterns are the cognitions the neurotransmitters are merely the domino effect to create the pattern and how quick you can get a pattern to show up.