76 replies to this topic

[JayZin]

http://area1255.blog...production.html

[Junk Master]

In this anti-prescription drug climate, U.S. at least, I can't imagine walking in and asking a Doc for Desoxyn!  The only thing that would be worse is asking for Oxy.

 

 

[thedevinroy]

http://area1255.blog...production.html

 

Yeah... but higher basal brain cAMP is contraindicated for concentration.  Perhaps if it is only presynaptic, no problem, and in fact it might increase the signal/noise ratio.  However, it seems to cross the BBB...

 

https://www.reddit.c...iltep_debunked/

 

That's a fun read.

 

Increasing tyrosine hydroxylase for purposes of sustained attention, concentration, and motivation is kind of the direction I'd like to go in... Dopamine is great, cAMP is great, but they don't really help you concentrate without the cortical norepinephrine levels, too.  D1 and D4 receptors have similar effects to the Alpha1 (and arguably Alpha2, but only as a backup) adrenergic receptors.  D4 is the fun one.  BUT... without a LOT of stimulation from DA/NA, you are not going to overcome the signal noise ratio associated with increased cAMP (unless you are cAMP deficient, which is possible I guess).  Even caffeine, a weak PDE inhibitor, seems to cause problems in concentration above 100mg in me, so I doubt forskolin is going to really help the aspects that need work for day-to-day stuff.

 

On the other hand, you might be onto something for quality of life.  Let's say your neurons are fried from a life long ride along Stressor's Drive.  You're retired and feeling like age isn't just a number, like you're an old person now.  Then forskolin might pep you up, restore those glial cells to full function.  Hopefully by then, we'll have figured out what forskolin is actually good for in healthy and biologically older individuals.

[thedevinroy]

In this anti-prescription drug climate, U.S. at least, I can't imagine walking in and asking a Doc for Desoxyn!  The only thing that would be worse is asking for Oxy.

 

You've written exactly what I was thinking.  I mean I would honestly feel more comfortable picking out the supplier on the black market, then going through a trusted super chill, local street dealer, setting up a drop point, paying cash after making sure the seal hasn't been tampered with.  It's a lot of work, but it would be cheaper and take less time than going through the system to find out if it works as I need it to or just makes me high.  Fortunately/unfortunately, I don't know any dealers, and I'm not too motivated to go down that road.  If I did, though, still not interested.  Amphetamine salts were borderline effective for executive function, mostly.  

 

And then, of course, there is the fact that meth is more toxic, possibly even at ADHD treatment levels:

 

http://jpet.aspetjou...t/315/1/91.long

 

I'd rather not take my chances... not until some study comes out ruling the opposite is actually true.

[Junk Master]

Besides, if a measly 100mg of caffeine causes you concentration problems I'm guessing even a tiny dose of meth is going to send you into hypomania.  Or as it is often referred to here, the land of Isochroma.

[Mind_Paralysis]

@Junk Master: Medication-sensitivity, or to be accurate, dopamine and norepinephrine -sensitivity is not the plausible reason for why Devinthayer gets concentration-deficits from Caffeine - as he, and I, have already explained, naturally aberrantly enhanced cAMP-levels in the Pre-frontal-cortex is one of the noted pathophysiologies of ADHD.

(it's hard to tell if that is the case for SCT as well, since so much of the damn research is muddled up and gobbled together - mixing up results of both ADHD (dopaminergic) SCT (norepinephrinergic) and Unknown (cholinergic), but there's a strong possibility that it IS - since DRD4 -mutations are actually looking to be more connected to SCT than ADHD - DAT1, dopamine transport-mutations, appears to be the big contributor to ADHD-symptoms, which explains the efficacy of Methylphenidate - it affects DAT directly.).

Caffeine increases cAMP - neither MPH or AMP does that, because they hit the D4-receptors enough to start the signals to the NMDA-network which then directly lowers PFC-levels of cAMP.

I don't know why I have to keep repeating myself with this, but this is also the proposed mode of action of Intuniv, which uses g-protein coupled Alpha-2-A receptors to lower cAMP in a slightly longer feedback-loop.

With that said, Methamphetamine is NOT likely to be the golden compound that helps with SCT - as I've ALSO said, like twenty times over, traditional stimulants have a very limited response-rate on SCT-symptoms. Not to mention the fact that Meth is indeed one of the most neurotoxic of all frequently used drugs out there - it's just not a sustainable drug.

[JayZin]

@Junk Master: Medication-sensitivity, or to be accurate, dopamine and norepinephrine -sensitivity is not the plausible reason for why Devinthayer gets concentration-deficits from Caffeine - as he, and I, have already explained, naturally aberrantly enhanced cAMP-levels in the Pre-frontal-cortex is one of the noted pathophysiologies of ADHD.

(it's hard to tell if that is the case for SCT as well, since so much of the damn research is muddled up and gobbled together - mixing up results of both ADHD (dopaminergic) SCT (norepinephrinergic) and Unknown (cholinergic), but there's a strong possibility that it IS - since DRD4 -mutations are actually looking to be more connected to SCT than ADHD - DAT1, dopamine transport-mutations, appears to be the big contributor to ADHD-symptoms, which explains the efficacy of Methylphenidate - it affects DAT directly.).

 

Caffeine increases cAMP - neither MPH or AMP does that, because they hit the D4-receptors enough to start the signals to the NMDA-network which then directly lowers PFC-levels of cAMP.

 

I don't know why I have to keep repeating myself with this, but this is also the proposed mode of action of Intuniv, which uses g-protein coupled Alpha-2-A receptors to lower cAMP in a slightly longer feedback-loop.

 

With that said, Methamphetamine is NOT likely to be the golden compound that helps with SCT - as I've ALSO said, like twenty times over, traditional stimulants have a very limited response-rate on SCT-symptoms. Not to mention the fact that Meth is indeed one of the most neurotoxic of all frequently used drugs out there - it's just not a sustainable drug.

 

Amphetamine activates so much that increases cyclic AMP though, so that's not really a good argument. You say it activates D4R, and this leads to NMDAR-enhancement, that's not even totally true (actually not at all), a lot of research shows that NMDAR-phosphorylation is actually dependent on cAMP; so we'd actually want to elevate it to some extent.

http://www.ncbi.nlm..../pubmed/8799572

http://www.ncbi.nlm..../pubmed/9384514

http://www.ncbi.nlm....pubmed/12377393

 

 

J Neurosci. 2003 Oct 29;23(30):9852-61.

Regulation of NMDA receptors by dopamine D4 signaling in prefrontal cortex.

Wang X1, Zhong P, Gu Z, Yan Z.

Author information

 

Abstract

Increasing evidence has suggested that the interaction between dopaminergic and glutamatergic systems in prefrontal cortex (PFC) plays an important role in normal mental functions and neuropsychiatric disorders. In this study, we examined the regulation of NMDA-type glutamate receptors by the PFC dopamine D4 receptor (one of the principal targets of antipsychotic drugs). Application of the D4 receptor agonist PD168077 caused a reversible decrease of the NMDA receptor (NMDAR)-mediated current in acutely isolated and cultured PFC pyramidal neurons, an effect that was blocked by selective D4 receptor antagonists. Furthermore, application of PD168077 produced a potent reduction of the amplitude (but not paired-pulse ratio) of evoked NMDAR EPSCs in PFC slices. The D4 modulation of NMDA receptors in PFC involved the inhibition of protein kinase A, activation of protein phosphatase 1 and the ensuing inhibition of active Ca2+-calmodulin-dependent kinase II (CaMKII). Moreover, PD168077 reduced the surface expression of NMDARs and triggered the internalization of NMDARs in a manner dependent on CaMKII activity. These results identify a mechanistic link between D4 and NMDA receptors in PFC pyramidal neurons, suggesting that D4 receptors may play an important role in modulating synaptic plasticity and thus cognitive and emotional processes in PFC circuits.

PMID:   14586014

[PubMed - indexed for MEDLINE] Free full text

 

[Mind_Paralysis]

Amphetamine activates so much that increases cyclic AMP though, so that's not really a good argument. You say it activates D4R, and this leads to NMDAR-enhancement, that's not even totally true (actually not at all), a lot of research shows that NMDAR-phosphorylation is actually dependent on cAMP; so we'd actually want to elevate it to some extent.

http://www.ncbi.nlm..../pubmed/8799572

http://www.ncbi.nlm..../pubmed/9384514

http://www.ncbi.nlm....pubmed/12377393

 

 

J Neurosci. 2003 Oct 29;23(30):9852-61.

Regulation of NMDA receptors by dopamine D4 signaling in prefrontal cortex.

Wang X1, Zhong P, Gu Z, Yan Z.

Author information

 

Abstract

Increasing evidence has suggested that the interaction between dopaminergic and glutamatergic systems in prefrontal cortex (PFC) plays an important role in normal mental functions and neuropsychiatric disorders. In this study, we examined the regulation of NMDA-type glutamate receptors by the PFC dopamine D4 receptor (one of the principal targets of antipsychotic drugs). Application of the D4 receptor agonist PD168077 caused a reversible decrease of the NMDA receptor (NMDAR)-mediated current in acutely isolated and cultured PFC pyramidal neurons, an effect that was blocked by selective D4 receptor antagonists. Furthermore, application of PD168077 produced a potent reduction of the amplitude (but not paired-pulse ratio) of evoked NMDAR EPSCs in PFC slices. The D4 modulation of NMDA receptors in PFC involved the inhibition of protein kinase A, activation of protein phosphatase 1 and the ensuing inhibition of active Ca2+-calmodulin-dependent kinase II (CaMKII). Moreover, PD168077 reduced the surface expression of NMDARs and triggered the internalization of NMDARs in a manner dependent on CaMKII activity. These results identify a mechanistic link between D4 and NMDA receptors in PFC pyramidal neurons, suggesting that D4 receptors may play an important role in modulating synaptic plasticity and thus cognitive and emotional processes in PFC circuits.

PMID:   14586014

[PubMed - indexed for MEDLINE] Free full text

 

 

Maybe you're right Jayzin, and Amphetamine and Methylphenidate doesn't lower cAMP by hitting the D4-receptor (mainly because they increase GLOBAL dopamine, hence eventually they affect the D4-receptor, but only after hitting everything else repeatedly), but the receptor is certainly connected to cAMP regulation, and antagonizes the NMDA-network.

 

 

This is my train of thought:

 

1. The connection of D4 to inattention.

The dopamine D4 receptor is essential for hyperactivity and impaired behavioral inhibition in a mouse model of attention deficit/hyperactivity disorder

http://www.nature.co...l/4001474a.html

 

 

2. The trend of connection of DAT1 to ADHD, but DRD4 to ADD (SCT)

 

Attention-deficit disorder (attention-deficit/hyperactivity disorder without hyperactivity): A neurobiologically and behaviorally distinct disorder from attention-deficit/hyperactivity disorder (with hyperactivity)

http://www.ncbi.nlm....les/PMC1474811/

 

Consistent with an association between DRD4 polymorphism and ADD is Auerbach, Benjamin, Faroy, Geller, and Ebstein's finding (2001) of a significant relation between individual differences in sustained attention and working memory on the one hand and polymorphism of the DRD4 gene on the other hand in normal infants (those with the 7-repeat allele performing worse).

 

 

Dopamine DRD4 receptor polymorphism and attention deficit hyperactivity disorder.

http://www.ncbi.nlm..../pubmed/9774775

 

 

3. Connection between DRD4 and NMDA-receptors

 

Binding of NMDA receptor and DRD4

http://www.evexdb.or...events/2934258/

 

D4 dopamine receptors modulate NR2B NMDA receptors and LTP in stratum oriens of hippocampal CA1.

http://www.ncbi.nlm....pubmed/21955919

 

 

4. Proposed mode of action of Guanfacine in ADHD

Guanfacine: The Future for ADHD Treatment

http://www.yalescien...adhd-treatment/

 

The right amount of NE will properly stimulate postsynaptic alpha-2A receptors (figure 2) to inhibit cAMP (cyclic adenosine monophosphate) in PFC dendritic spines...With sufficient NE, the cAMP pathways are inhibited and the neuronal networks connect more effectively (figure 3)... found that guanfacine, which mimics NE at alpha-2A receptors, strengthens PFC regulation of behavior and attention.

 

 

Of course, this over-abundancy of cAMP is only a problem in the PFC, so that's where you want the antagonising action.

 

 

SO... are we on the same page here? I gotta' admit, my burnout-brain is getting a bit confused. Didn't I previously say that DRD4-receptors caused antagonistic signalling in the NMDA-network, hence leading to lowered cAMP, hence leading to better attention? Theoretically also explaining the effectiveness of Memantine as ADHD -treatment.

Did you agree with that, or DISagree?

I apologize if these questions are repetitive or annoying, but I have been burnt-out for 3 hours, and attempting to answer you for approximately 1,5 hours.

[JayZin]

Of course, this over-abundancy of cAMP is only a problem in the PFC, so that's where you want the antagonising action.
 
 
SO... are we on the same page here? I gotta' admit, my burnout-brain is getting a bit confused. Didn't I previously say that DRD4-receptors caused antagonistic signalling in the NMDA-network, hence leading to lowered cAMP, hence leading to better attention? Theoretically also explaining the effectiveness of Memantine as ADHD -treatment.

Did you agree with that, or DISagree?

I apologize if these questions are repetitive or annoying, but I have been burnt-out for 3 hours, and attempting to answer you for approximately 1,5 hours.

I think it was just miscommunication, before you stated D4R activation ''starts the signals to NMDA'' which would be inaccurate. Tbh I think we are on the same page, that was minor hiccup, that's all.

Cyclic AMP plays a role in oxidative stress, immunity, inflammation, susceptibility to asthma and others as well, so it's not just about brain health - if we have low cAMP we become very susceptible to asthma/allergies, chronic itching, obsessive behaviors and even psychotic thinking in a small number of affected individuals. At the same time, the connection between cAMP and brain health may be related to it's actions in the atrium, in the heart, there is affects sinoatrial node with some relation to vagus nerve activity as well as then heart rate - corresponding somewhat to blood flow and oxygen consumption/utilization.

 

http://www.ncbi.nlm....pubmed/18418428

http://www.ncbi.nlm....cles/PMC302397/

http://www.ncbi.nlm....les/PMC1553238/

http://jgp.rupress.o.../136/3/237.full

http://www.ncbi.nlm..../pubmed/1963221

[Mind_Paralysis]

Interesting. I have never actually had my cAMP -levels checked - I have no idea how one would go about doing that, in the CNS, non-invasively.

 

I do know that I am inattentive and yet I still have both Allergies and Asthma - allergy-triggered Asthma even! So, obviously it's not a global effect, should my cAMP -levels be elevated.

[JayZin]

I'd be interested in trying Rolipram to see how it affects hormones and cognition.

Though Dipyridamole would have similar effects.

[thedevinroy]

http://www.sciencedi...303720714001361

Looks like PDE2 inhibition leads to a TH reduction from adenosine agonism.

Although from what I understand about PDE4 inhibition is that it also has a similar effect.

Adenosine blockers like caffeine seem to have their own effect on PDE release and therefore tyrosine hydroxylase over time (though not initially) that maybe we need to take a closer look at.


Sent from my iPhone using Tapatalk

[JayZin]

I've been using Donepezil as an experiment lately, it's definitely 5x stronger than Huperzine A. I bought it from HERE {https://www.napsgear...roducts_id=1895}.

[Mind_Paralysis]

http://www.sciencedi...303720714001361

Looks like PDE2 inhibition leads to a TH reduction from adenosine agonism.

Although from what I understand about PDE4 inhibition is that it also has a similar effect.

Adenosine blockers like caffeine seem to have their own effect on PDE release and therefore tyrosine hydroxylase over time (though not initially) that maybe we need to take a closer look at.


Sent from my iPhone using Tapatalk

 

What would the effect be though? Increased or lowered Hydroxylase? And how powerful a Adenosine blocker is Caffeine? If it's a decent one, I'm not sure how useful looking into that is, since Caffeine hasn't been proven as a valid treatment of both hyperactive and inattentive adhd. (which is the only recognized attention-disorder at this time)

 

If caffeine really had a positive long-term effect on these symptoms, then it would have become a staple in treatment a long time ago - I mean, caffeine-use is sooo common.

 

Of course, if there are adenosine blockers with far greater efficacy than Caffeine, then it might be worth a look.

 

Are any of the peripheral side-effects of caffeine related to the Adenosine blockage, btw?

[thedevinroy]

http://www.sciencedi...303720714001361

Looks like PDE2 inhibition leads to a TH reduction from adenosine agonism.

Although from what I understand about PDE4 inhibition is that it also has a similar effect.

Adenosine blockers like caffeine seem to have their own effect on PDE release and therefore tyrosine hydroxylase over time (though not initially) that maybe we need to take a closer look at.


Sent from my iPhone using Tapatalk

What would the effect be though? Increased or lowered Hydroxylase? And how powerful a Adenosine blocker is Caffeine? If it's a decent one, I'm not sure how useful looking into that is, since Caffeine hasn't been proven as a valid treatment of both hyperactive and inattentive adhd. (which is the only recognized attention-disorder at this time)

If caffeine really had a positive long-term effect on these symptoms, then it would have become a staple in treatment a long time ago - I mean, caffeine-use is sooo common.

Of course, if there are adenosine blockers with far greater efficacy than Caffeine, then it might be worth a look.

Are any of the peripheral side-effects of caffeine related to the Adenosine blockage, btw?

By over time I mean from repeated use throughout the day. The initial burst of energy and fog removal is nice, but then it subsides. You have your second cup of coffee or energy drink, and it makes you hyperactive. I always wondered why that was. I thought maybe it was from increased cAMP, but now I'm thinking it might be from increased cAMP in the wrong places.

[Mind_Paralysis]

 

 

http://www.sciencedi...303720714001361

Looks like PDE2 inhibition leads to a TH reduction from adenosine agonism.

Although from what I understand about PDE4 inhibition is that it also has a similar effect.

Adenosine blockers like caffeine seem to have their own effect on PDE release and therefore tyrosine hydroxylase over time (though not initially) that maybe we need to take a closer look at.


Sent from my iPhone using Tapatalk

What would the effect be though? Increased or lowered Hydroxylase? And how powerful a Adenosine blocker is Caffeine? If it's a decent one, I'm not sure how useful looking into that is, since Caffeine hasn't been proven as a valid treatment of both hyperactive and inattentive adhd. (which is the only recognized attention-disorder at this time)

If caffeine really had a positive long-term effect on these symptoms, then it would have become a staple in treatment a long time ago - I mean, caffeine-use is sooo common.

Of course, if there are adenosine blockers with far greater efficacy than Caffeine, then it might be worth a look.

Are any of the peripheral side-effects of caffeine related to the Adenosine blockage, btw?

By over time I mean from repeated use throughout the day. The initial burst of energy and fog removal is nice, but then it subsides. You have your second cup of coffee or energy drink, and it makes you hyperactive. I always wondered why that was. I thought maybe it was from increased cAMP, but now I'm thinking it might be from increased cAMP in the wrong places.

 

 

Well, increased cAMP in the PFC *is* the wrong place, so sure.

[Nate-2004]

This is a very interesting thread on increasing Tyrosine Hydroxylase. I've been trying to find ways to improve my libido, I happen to have lithium oroate but not sure if I should try it.