16 replies to this topic

[noot_in_the_sky]

I just got an idea for a stack making dopamine receptors more sensitive.


Dopamine Sensitivity:

Diets enriched in foods with high antioxidant activity reverse age-induced decreases in cerebellar beta-adrenergic function and increases in proinflammatory cytokines.

Gemma C, Mesches MH, Sepesi B, Choo K, Holmes DB, Bickford PC.
James A. Haley Veterans Affairs Medical Center, Tampa, Florida 33612, USA.


Antioxidants and diets supplemented with foods high in oxygen radical absorbance capacity (ORAC) reverse age-related decreases in cerebellar beta-adrenergic receptor function. We examined whether this effect was related to the antioxidant capacity of the food supplement and whether an antioxidant-rich diet reduced the levels of proinflammatory cytokines in the cerebellum. Aged male Fischer 344 rats were given apple (5 mg dry weight), spirulina (5 mg), or cucumber (5 mg) either in 0.5 ml water by oral gavage or supplied in the rat chow daily for 14 d. Electrophysiologic techniques revealed a significant decrease in beta-adrenergic receptor function in aged control rats. Spirulina reversed this effect. Apple (a food with intermediate ORAC) had an intermediate effect on cerebellar beta-adrenergic receptor physiology, and cucumber (low ORAC) had no effect, indicating that the reversal of beta-adrenergic receptor function decreases might be related to the ORAC dose. The mRNA of the proinflammatory cytokines tumor necrosis factor-alpha (TNFalpha) and TNFbeta was also examined. RNase protection assays revealed increased levels of these cytokines in the aged cerebellum. Spirulina and apple significantly downregulated this age-related increase in proinflammatory cytokines, whereas cucumber had no effect, suggesting that one mechanism by which these diets work is by modulation of an age-related increase in inflammatory responses. Malondialdehyde (MDA) was measured as a marker of oxidative damage. Apple and spirulina but not cucumber decreased MDA levels in the aged rats. In summary, the improved beta-adrenergic receptor function in aged rats induced by diets rich in antioxidants is related to the ORAC dose, and these diets reduce proinflammatory cytokine levels.

Delayed inhibition of dopamine synthesis by gamma-butyrolactone and baclofen: dopamine autoreceptor supersensitivity?

Argiolas A, Fadda F, Melis MR, Marcou M, Porceddu ML, Gessa GL.


The administration of gamma-butyrolactone (GBL) (750 mg . kg-1 i.p.) and baclofen (20 mg . kg-1 i.p.) to rats caused a transient increase followed by a long-lasting decrease in striatal dopamine (DA) synthesis, as measured by DOPA accumulation after decarboxylase inhibition. DA synthesis was reduced to 40-50% of the control value for 2-12 h following either treatment. The GBL- and baclofen-induced inhibition of DN synthesis was reversed by haloperidol (2-5 mg . kg-1 i.p.) and by a second dose of baclofen or GBL. The subcutaneous dose of 15 mg . kg-1 of apomorphine, insufficient to decrease DA synthesis in control rats, produced a further decrease in DA synthesis in animals pretreated with baclofen. These results suggest that the delayed DA synthesis inhibition following GBL or baclofen treatment was due to stimulation of supersensitive DA autoreceptors.

Dopamine modulates the inhibition induced by GABA in rat cerebral cortex: an iontophoretic study.

Beauregard M, Ferron A.
Departement de Physiologie, Faculte de Medecine, Universite de Montreal, Quebec, Canada.


Effects of iontophoresed gamma-aminobutyric acid (GABA) and two GABA agonists, 4,5,6,7-tetrahydroisooxazolo-[5,4-c]pyridine-3-ol (THIP) and baclofen were quantitatively compared in the anterior cingulate, frontal, and parietal cortex of urethane-anesthetized intact rats after catecholamine (CA) depletion with alpha-methyl-p-tyrosine (alpha-MPT) or selective dopamine (DA) denervation with 6-hydroxydopamine (6-OHDA). As assessed with to the IT50 index, the postsynaptic sensitivity to GABA was significantly higher in anterior cingulate than in frontal and parietal cortex. The responsiveness to GABA was also greater in frontal than in parietal cortex. Sensitivity to GABA was significantly reduced in both anterior cingulate and frontal cortex after CA depletion, and similarly, after DA denervation with 6-OHDA. The difference in the sensitivity to GABA between the three cortical regions in intact rats as well as after CA depletion did not seem to be correlated with either GABAA or GABAB receptors since the responsiveness to both GABA agonists in every region examined was comparable in intact rats, and remained unchanged after alpha-MPT treatment. This finding raises the possibility that some GABA receptors in the cerebral cortex may be pharmacologically distinct from the two main subtypes of GABA receptors, GABAA and GABAB. When GABA was administered by iontophoresis in the anterior cingulate cortex during continuous applications of subthreshold currents of DA, the inhibition induced by GABA was either increased or decreased. As DA innervation density is nearly two-fold greater in anterior cingulate than in frontal cortex, and 30-fold greater in anterior cingulate than in parietal cortex, these results suggest that responsiveness to GABA may be correlated with the regional density of DA innervation and that elevated levels of DA may enhance the sensitivity to GABA.

This is a possible stack:

Step 1 protect Dopamine receptors.
Take antioxidantes permanitly.

Step 2 increase Dopamine receptors.
Sulbutamine and CDP-Choline, for about a month or 2.

Step 3 make dopamine receptors sensitiv:
A GABA agonist Picamilon, Phenibut, Ashwagandha, l-theanine, or lemon balm(melissa), for about month.

Step 4
Rest from Step 2 and 3, and take a DRI as needed.

Step 5
Cycle Step 2, 3, and 4.

List of DRI:

Amineptine (Has been remove from the market in most parts of the world.)
Altropane (O-587)
Amfonelic acid (WIN 25978)
BTCP (GK-13)
DBL-583
Difluoropine (O-620)
GBR-12935
GYKI-52895
Iometopane (β-CIT, RTI-55)
Medifoxamine
RTI-229
Vanoxerine (GBR-12909)

Natural DRI:
Chaenomeles speciosa (Flowering Quince, Mu gua)
Hyperforin, Adhyperforin (2 counponts of St. John's Wort)

What's your take on this?

Edited by noot_in_the_sky, 27 May 2013 - 02:16 PM.

[socialpiranha]

Not sure what the increased beta adrenergic function has to do with dopamine receptor sensitivity. Dopamine receptor sensitivity might be an issue worth looking into but i highly doubt any of the substances you mentioned(that are obtainable) increase dopamine sensitivity except maybe phenibut. Receptor sensitivity might be too complex though and oversensitivity(either too often or too much) might lead to tolerance andwithdrawal symptoms etc. just look at ghb, gbl and phenibut experiences they all start out as glowing reports and end up "another (blank) casualty".

That being said it is still an avenue worth looking into. Try to find some studies about legally obtainable substances that affect dopamine sensitivity without causing withdrawal. baclofen might be worth a try, although i tried it and didnt notice any positive effects. maybe i didnt take it long enough though i dunno.

keep theorizing and go deeper!

dopamine idea tho bro

[noot_in_the_sky]

Thanks for your input. I have read some of the stories of phenibut, which is way I was mainly thinking on something like picamilon, or perhaps something a little more mild. This baclofen sounds interesting I'll take a look at it.

I'll keep going deeper and see what I can discover.

[socialpiranha]

I'll keep going deeper and see what I can discover.

awesome, the deeper you go the closer you get! It's good to have company


From my own research into my own issues it seems like dopamine sensitivity plays a role but is very complex. Hypersensitivity in some brain areas is implicated in schizophrenia and in others it causes euphoria or even sedation.

I dunno what your symptoms are but i've been around the scene for a while and everyone seems to have the same disorder just with slight variations. The core symptoms are anhedonia, asthenia, and trouble controlling thoughts/attention. the latter seems to be the biggest variable and can manifest as either schizophrenia, bipolar, adhd, ocd, autism, generalized anxiety, or specific phobia.

The first two symptoms seem to be a staple for the most part, i think they are symptoms of long term inability to control thought/attention. Controlling thought/attention takes a huge amount of energy even for healthy people so unhealthy people are bound to become exhausted and unmotivated eventually. Energy and motivation go hand in hand with the ability to focus on one thing as opposed to another which is why stimulants have the best results overall at least until they stop working.

Exercise and eating well is beneficial in all of these disorders unfortunately the disorder itself often disables a person to a point where its not possible. What stimulants and healthy living have in common is allowing the brain/body to function at peak performance, this gives you the ability to have greater control over your thoughts. The problem with stimulants is that it simulates having optimum food intake and exercise without actually having it. This is why you get the crash and eventual lack of effect. They also can cause paradoxical effects because the stimulation is so general. The problem with eating well and exercising is its extremely hard if not impossible to do or maintain in lots of cases.

I don't know yet what the solution is, but some possible scenarios are

Using stimulants in order to eat well and exercise long enough to make it a solid habit.

Using stimulants and selective depressants in order to curb specific symptoms and therefore be able to exercise and eat well.

finding a totally attention selective substance

finding a substance which alters the genes which predispose a person to have an attention deficit


I would like to see all mental health disorders under the umbrella of attention deficit disorder with subtypes according to differing symptoms. No matter what the symptom the problem is always the inability to focus on something else instead, that is the difference between healthy and unhealthy people.

[xks201]

In studies I have read, beta adrenergic agonists have been known to increase dopaminergic functioning.


socialpiranha, have you tried any of the glucocorticoid sensitivity enhancing drugs you mentioned in another thread such as celicoxib, rolipram, and iccarin?

[socialpiranha]

I tried icariin, it has potent fast acting antidepressant effects but it gives me a really panicky feeling in my chest so i set it aside for now. Haven't tried rolipram or celecoxib yet i plan to though. Might try luteolin first (pde4 inhibitor like rolipram) just because im so tired of asking my dr for prescriptions.

[Patrick Sylvester]

I have read some of the stories of phenibut

phenibut does seem unpredictable and understudied from what little i've gathered. i really like your idea and it's clarity. something i was looking at earlier, (a thread where someone wanted to use antagonist at night to create natural agonism during the day for 5HT & DA) apparently Tianeptine could help via an indirect method :

...Basically what I'm saying is that DA and 5-HT behave in completely different ways to opioids, and it is a gross oversimplification to believe that they can be manipulated in the same way that opioids can.

Saying that, receptor up-regulation is still a tertiary response to a moderate decrease in DA or 5-HT ardency, and increased sensitivity can be enabled though a somewhat similar mechanism with a different dynamic.

Neuroleptics are DA antagonists, but their MOA tends to increase the activity of tyrosine hydroxylase, rather then receptor density , and so they will typically not facilitate the response you want, at least not at typical dosing levels. With prolonged low dose exposure however they can act in a way that would be enabling to an increase in dopamine sensitivity .

Sulbutiamine induces an increase in the density of D1 dopamine receptors in the prefrontal cortex due to a reduction in the release of dopamine. But because it has a positively charged thiazole moiety it can only be transported across the plasma membrane of dopaminergic neurons by high affinity carriers, what this means, especially in the brain because of it's anion activity, is that the rate of transport tends to fluctuate. So that you get an oscillation of dopamine release in the cortex, over a prolonged period (a few weeks) this oscillation will be compensated for through reactionary changes in endogenous dopamine production. The net result being the sulbutiamine's effectiveness will become negligible, and you'll be left with a dystonic dopaminergic system.

With regards to dopamine, agonists (particularly D1) are your best bet, but they are difficult to procure.

Serotonin on the other hand already has a novel sensitization agent in the form of Tianeptine (Stablon), a beautiful mo lecule which not only facilitates an increase in the density of serotonin receptors, it also increases activity of dopamine in the striatum, thus increasing the explicit activity of spiny GABA-ergic projection neurons, giving rise t o anxiolysis and mood enhancement (through the increase in GABA-B). Tianeptine also enhances the affinity of the D2 and D3 dopamine receptors for their ligand through minor conformational changes, once again improving your feelings of well-being markedly.

So options are:

Dopamine - Sub theraputic doses of a neuroleptic (I recommend sulpride) OR weekly cycling of sulbutiamine with a dopamine precursor such as L-Tyrosine....

Tianeptine
SSRE

Tianeptine is a selective serotonin reuptake enhancer...
Tianeptine enhances the extracellular concentration of dopamine in the nucleus accumbens and modulates the D₂ and D₃ dopamine receptors...
In contrast to SSRIs and tricyclic antidepressants, tianeptine modestly enhances the mesolimbic release of dopamine and potentiates CNS D2 and D3 receptors, but it is also unclear how this occurs because tiapentine has no affinity for the dopamine transporter or the dopamine receptors D1, D2, D3, D4 and D5

Amineptine, the most closely related drug to have been widely studied, is a dopamine reuptake inhibitor with no significant effect on serotonin levels (conversely, tianeptine has no affinity for the dopamine transporter).

[Thorsten3]

I tried icariin, it has potent fast acting antidepressant effects but it gives me a really panicky feeling in my chest so i set it aside for now. Haven't tried rolipram or celecoxib yet i plan to though. Might try luteolin first (pde4 inhibitor like rolipram) just because im so tired of asking my dr for prescriptions.

Horny goat weed isn't even used in Chinese medicine very often, without yin cooling herbs, to balance out its extremely yang nature. It will result in you burning out quite quickly, if you choos to use it chronically (for most I have heard about). It's real easy to overdose on it, it's that powerful.

I know icariin is only one of a few constituents that make up the compound, but, I have taken it as a standalone agent and it certainly has that red, fiery yang aspect to it, too. It was incredibly mood lifting for the first couple of days then that subsided into road rage, aggression and a irritable mind. Like panax ginseng, I can see how it might provoke anxiogenic states, too.

[noot_in_the_sky]

Tianeptine help ease depression, ED, asthma and increase NMDA and AMPA receptors. This thing sound like a fascinating medication, I wounder why it isn't more popular?

I like the fact that it has such a short-half life. Thus shorting the life-time of any side-effect.

Something I forgot to add to the my first post is the possible use of Selegiline or some other MAOB inhibitor. We can substituting a DRI with this or perhaps combine it with a weak DRI, but I'm still bit worry about combining them.

[Patrick Sylvester]

(-)-1-(Benzofuran-2-yl)-2-propylaminopentane ((-)-BPAP)^[1] is a drug with an unusual effects profile. It can loosely be grouped with the stimulant or antidepressant drug families, but its mechanism of action is quite different.
BPAP (along with another similar compound PPAP) is classified as a catecholaminergic and serotonergic activity enhancer. This me ans that it stimulates the impulse propagation mediated transmitter release of the neurotransmitters dopamine, norepinephrine and serotonin in the brain. However, unlike stimulant drugs like amphetamine, which release a flood of these neurotransmitters in an uncontrolled manner, BPAP instead only increases the amount of neurotransmitter that gets released when a neuron is stimulated by receiving an impulse from a neighbouring neuron. So while both amphetamine and BPAP increase the amount of neurotransmitters that get released, amphetamine causes neurons to dump neurotransmitter stores into the synapse regardless of external input, while with BPAP the pattern of neurotransmitter release is not changed, but when the neuron would normally release neurotransmitter, a larger amount than normal is released.
Other drugs which produce this effect are the endogenous trace amines phenethylamine (PEA) and tryptamine, and the neuroprotective MAO-B inhibitor selegiline. However, while selegiline is a potent monoamine oxidase inhibitor, BPAP is only a weak MAO-A inhibitor at high doses, and at low doses produces only the activity enhancer effect.
BPAP has been shown to have neuroprotective effects similar to those of selegiline, and has been researched for the treatment of Alzheimer's disease, Parkinson's disease and clinical depression.

I read somewhere that combining this with deprenyl (selegiline) resulted in intense concentration and great mood for 6 hours with no comedown. It's easy to synthesize and 1 gram should last a couple of years.

This was the next compound researched by Dr. Knoll that was better suited for longevity purposes.

BPAP
(-)BPAP
(-)-BPAP GB

step 2 : CDP Choline

[Area-1255]

Not sure what the increased beta adrenergic function has to do with dopamine receptor sensitivity. Dopamine receptor sensitivity might be an issue worth looking into but i highly doubt any of the substances you mentioned(that are obtainable) increase dopamine sensitivity except maybe phenibut. Receptor sensitivity might be too complex though and oversensitivity(either too often or too much) might lead to tolerance andwithdrawal symptoms etc. just look at ghb, gbl and phenibut experiences they all start out as glowing reports and end up "another (blank) casualty".

That being said it is still an avenue worth looking into. Try to find some studies about legally obtainable substances that affect dopamine sensitivity without causing withdrawal. baclofen might be worth a try, although i tried it and didnt notice any positive effects. maybe i didnt take it long enough though i dunno.

keep theorizing and go deeper!

dopamine idea tho bro

ANYTHING that raises thyroid hormone, cyclic AMP, inhibits phosphodiesterases, or activates beta-adrenergic receptors - directly or indirectly, will stimulate tyrosine hydroxylase = more dopamine production from aminos. Vitamin D, E and testosterone also upregulates TH; tyrosine hydroxylase.

[forexworld12]

I do have ahnedonia and PSSD - downregulated/less sensitive dopamine receptor and I tried aswagandha and bacopa for 3 days -- they made me TOO MUCH irritable like i had to quit it.. Too much burning rage on silly and small things.. sometimes like acid refulx .. I still feel the irritation effects after 30 hours .I was taking like 1500mg aswagandha 2x a day and 300 mh bacopa 2x a day And it made the libido and penis sensation worse...I don't understand how does aswagandha make dopamine more sensitive ? I don't know if I should lower the dosage or quit it.. 

I guess the irritation is caused by acetylcholine increase which CDP choline does too - it can also induce depression so i was thinking if i can take something to block acetylcholine..

Edited by forexworld12, 03 November 2014 - 09:14 AM.

[jonnyD]

I do have ahnedonia and PSSD - downregulated/less sensitive dopamine receptor and I tried aswagandha and bacopa for 3 days -- they made me TOO MUCH irritable like i had to quit it.. Too much burning rage on silly and small things.. sometimes like acid refulx .. I still feel the irritation effects after 30 hours .I was taking like 1500mg aswagandha 2x a day and 300 mh bacopa 2x a day And it made the libido and penis sensation worse...I don't understand how does aswagandha make dopamine more sensitive ? I don't know if I should lower the dosage or quit it..
I guess the irritation is caused by acetylcholine increase which CDP choline does too - it can also induce depression so i was thinking if i can take something to block acetylcholine..

Try ashwaghanda without bacopa. I am getting the same negative effects from bacopa but only good effects from ashwaghanda.

[forexworld12]

 

I do have ahnedonia and PSSD - downregulated/less sensitive dopamine receptor and I tried aswagandha and bacopa for 3 days -- they made me TOO MUCH irritable like i had to quit it.. Too much burning rage on silly and small things.. sometimes like acid refulx .. I still feel the irritation effects after 30 hours .I was taking like 1500mg aswagandha 2x a day and 300 mh bacopa 2x a day And it made the libido and penis sensation worse...I don't understand how does aswagandha make dopamine more sensitive ? I don't know if I should lower the dosage or quit it..
I guess the irritation is caused by acetylcholine increase which CDP choline does too - it can also induce depression so i was thinking if i can take something to block acetylcholine..

Try ashwaghanda without bacopa. I am getting the same negative effects from bacopa but only good effects from ashwaghanda.

 

thanks man will do that !

[forexworld12]

3 days alone on aswagandha and it does the same makes me irritable and more numb .. It was suppose to do the opposite I guess . !

Edited by forexworld12, 05 November 2014 - 05:28 AM.

[Dichotohmy]

Even just a mild dose (600mg) of Ashwaghanda once a day made me more fatigued and zombie-like, while taking it at night seemed to make my sleep even worse, so count me in as another Ashwaghanda non-responder.

 

Intuitively, I think antioxidants might be an effective and side-effect free course of action to slowly upregulating dopaminergic functioning. I have to stress the glacial pace at which the dopaminergic system upregulates. I've gotten better results to this end with Ascorbic acid, Japanese knotweed (resveratrol), and NAC in my stack than I've gotten from "activating" supplements like Rhodiola or Eleuthro, and better results without tolerance than from gray-market pharmaceuticals like Tianeptine or Selegiline.  

[forexworld12]

Even just a mild dose (600mg) of Ashwaghanda once a day made me more fatigued and zombie-like, while taking it at night seemed to make my sleep even worse, so count me in as another Ashwaghanda non-responder.

 

Intuitively, I think antioxidants might be an effective and side-effect free course of action to slowly upregulating dopaminergic functioning. I have to stress the glacial pace at which the dopaminergic system upregulates. I've gotten better results to this end with Ascorbic acid, Japanese knotweed (resveratrol), and NAC in my stack than I've gotten from "activating" supplements like Rhodiola or Eleuthro, and better results without tolerance than from gray-market pharmaceuticals like Tianeptine or Selegiline.  

If you would have to rate the term "better" in terms of % value out of 100(meaning absolute normal) from drugs like tianpetine and selegine how much % would u rate them ?