Re-Igniting and (Possibly) Finishing the Search for the "Dopaminergic Pot of Gold"

WARNING : Everything you read here is theoretical and for educational purposes, you may read and absorb, but do not take the methods literally. If you happen to do this, you should understand the potential side effects (behavioral changes, blood pressure elevation and delirium). I do not recommend anyone try this concept in it's entirety until you know how each bit and part will affect YOU. Just because the concept may work for me or someone else, doesn't mean it will benefit YOU. 

:::::Maximizing GABA is ESSENTIAL to this, you will get anxiety if you don't keep your Adrenaline in Check::::

!!! This does not mean take massive doses of KLONOPINE or XANAX !!!

It means, naturally do everything to keep your GABA levels elevated, or do what it takes to keep GABA elevated. Otherwise these methods will not work properly.

One more thing, it is absolutely essential that you keep an Anti-Nausea drug - namely ZOFRAN on hand while experimenting. 
In fact DO NOT even BEGIN the application of ANY of this without that drug, you might want to take Zofran before even using the first compound. 

The GOAL of the Dopaminergic Pot of Gold, is to create a Euphoric and Intelligent state, resembling that of a Amphetamine Rush perhaps, but while maintaining BP and a healthy heart. This state of mind may rapidly increase feelings of Unlimited Power, and Invincibility, and will enhance your body and mind to a state - unprecedented. It represents one part of a "Perfect Chemistry". 

Read the WHOLE ARTICLE, and the Citations. 

I was reading through a topic on "Dr.Bob" one day ; a long discussion about the recreational/intentional enhancement of dopamine levels, it was interesting to find they had referred to this premise as "The Dopaminergic Pot of Gold". This isn't the first time it has been brought up either - people seem to see Dopamine as being an all-powerful neurohormone that transforms your conscience into that of a deity. Bluelight and psychedelic forums are two other notable discussion area's where I've seen this brought up.
I don't disagree. People have been trying to dig up this kind of information for a long ass time.

IN FACT, I am one of them, you might even say I've gone "above and beyond", being a natural perfectionist - I've longed to see the results of dopaminergic enhancement through every possible mechanism.

One is described below.
5-HT2A antagonism, now what does this do?
Well 5-HT receptors are SEROTONIN receptors, the 5-HT2A/2C are inhibitory upon dopaminergic neurotransmission - "notably in reward area's such as the Ventral Tagament (VTA) and Hypothalamus". The activation of these receptors are associated with increases in cortisol and prolactin - which also lower dopamine levels.

Besides enhancing dopamine, 5-HT2A/2C blockade is useful for another reason. Lowering Blood Pressure.
You see, when you activate 5-HT2A/2C - this in turn activates Phospholipase C and Protein Kinase C - both of these are vasoconstricting enzymes. (2)(3)(4)

We wouldn't want to have High Dopamine and high blood pressure anyway - would we? Depending on your Dopamine > Norepinephrine (NORadrenaline) conversion, this might under normal "dopamine enhancing circumstances" become a reality.

Posted by Brainbeard on July 2, 2009, at 16:14:09
 At the end of the rainbow? Perhaps. It has only lately occurred to me that, in my desperate and frantic searching for a way to enhance dopaminergic functioning, I have overlooked or at least wasn't aware of a particular way of raising dopamine (DA) (and noradrenaline (NA)) levels and/or firing, namely 5HT2A/C-antagonism. Stephen Stahl opened my eyes. I knew that a low dose of Prozac raises DA (and NA) levels in crucial parts of the brain, but I didn't know it did that because of 5HT2C-antagonism. I've experienced that low dose Risperdal, which I thought was supposed to help with anxiety, turned me into a social superman besides boosting my 'mental libido' (the part between the ears as opposed to what's going on below the belt) - without doing much for anxiety. I now understand that because of Risperdal's 5HT2A-antagonism, it indeed elevates dopamine levels, resulting in mentioned phenomena. There is a nice presentation by Stahl on the web where he explains how 5HT2A and -C-antagonism result in increased dopamine release. I can't give a direct link because it seems to be a subscription page; nevertheless, when you follow the following link and click on the first search result, you do end up in the presentation: http://www.google.nl/search?hl=nl&safe=active&rlz=1B3GGGL_nlNL255NL258&q=Schizophrenia%3A+From+Circuits+to+Symptoms+Presented+by+Stephen+M.+Stahl&btnG=Zoeken&meta= Quoting from the presentation: 'What receptor properties can enhance the ability of an atypical to improve mood and cognition? What does the 5HT2A antagonist property have to do with that? Normally, the serotonin neuron (...) talks to the dopamine and norepinephrine neurons and tells them to be quiet, to step on the brake. If you interfere with that, you don't inhibit anymore; and, if you don't inhibit anymore, you disinhibit, which is a fancy way of saying, "turning it on." So, to disinhibit means not another way to do it, but rather to turn things on. If you block the natural ability of serotonin to stop norepinephrine and dopamine release, you enable the dopamine and the norepinephrine to be released. So blocking this causes release.' And: 'What other receptor binding properties might enhance this ability, besides those of 5HT2A? We get into some speculation, but useful speculation. The 5HT2C receptor is also connected to the dopamine and to the norepinephrine neurons, and it also reduces those through gamma-aminobutyric acid (GABA) interneurons; if you block them, it also increases dopamine and norepinephrine.' For this reason, Stahl explains, low doses of both Prozac (fluoxetine) and ziprasidone (Geodon) can be activating, because they block 5HT2C and/or 5HT2A without much (or any) serotonergic (Prozac) or antidopaminergic (Geodon) action going on. Furthermore, 5HT1A-agonism seems to be essential to complete the trick: 'Any other properties? The 5HT1A agonist properties could be useful. Presynaptic actions could help antidepressant effects, and postsynaptic actions could help cognitive effects. Dr. Meltzer has done seminal work showing that you don't get these increases -- of the good, smart neurotransmitters of dopamine and norepinephrine, particularly dopamine -- unless you work through a 5HT1A receptor.' Stahl gives extensive descriptions of these phenomena in his Essential Psychopharmacology, fragments of which can be read on the web, for instance here: http://books.google.nl/books?id=cWbYxSfKN3cC&pg=PA351&dq=Stephen+Stahl+5HT2A-antagonism+dopamine+5HT1A+serotonin In Depression And Bipolar Disorder, he explains the link between 5HT1A-agonism and 5HT2A/C mediated DA release: http://books.google.nl/books?id=zqvVZOea2JAC&pg=PA120&dq=Stahl++stimulation+of+serotonin+1A+receptors+acutely+reduces+the+serotonergic+inhibition+of+DA (read the text UNDER the small text belonging to the picture). Here's a research abstract that shows that 5HT2A-antagonism revives SSRI-decreased noradrenergic firing: http://www.journals.elsevierhealth.com/periodicals/bps/article/PIIS0006322306006597/abstract So, all the moaning and whining about SSRI-induced apathy could once and for all be abolished if SSRIs would standardly get served with 5HT2A/C blockade plus 5HT1A-agonism. And this is where things get dirty. There ARE pure 5HT2A and/or -C antagonists, but they don't have enough marketing potential since as stand-alone's they're not very impressive. So they are only known under desperately unimaginative names like SR46349-B. The 5HT2A/C-blockers that HAVE been marketed are for the bigger part pretty dirty drugs, which is to day, they have affinity for a range of receptors and do a dozen of things simultaneously, often in a dose-related manner. The atypical antipsychotics (AAP's) are almost all characterized by 5HT2A-blockade. See this table for a comparison of antipsychotic beinding data: http://www.nature.com/npp/journal/v28/n3/fig_tab/1300027t1.html Risperdal, mentioned earlier, is a potent 5HT2A-blocker, but because it crosses the blood-brain-barrier, even at low doses it raises prolactin levels wildly. Let me assure you, hyperprolactinemia is not something to take lightly. 


It can cause tumors or make your bones brittle. In my case, it leads to gynecomastia, which isn't fun when you're not a travestite with Pamela Anderson as your role model. Zyprexa is an excellent 5HT2A and -C-blocker, but it's a much too strong antihistaminergic - what use is extra DA and NA when you're sleeping all day - and strongly diabetogenic on top of that. Geodon (ziprasidone) is an interesting candidate since it's a strong 5HT2A-blocker, a relatively strong 5HT2C-blocker, a weaker 5HT1A-agonist, AND its antagonistic touch of D2 is soft enough not to raise prolactin levels much or cause extrapyramidal symptoms even at therapeutic doses. Geodon is also a moderately strong serotonin and noadrenaline reuptake blocker. Stahl refers to it as sort of a mini-Effexor. Its withdrawal syndrome, though, doesn't seem to be very mini if you may believe the anecdotal evidence. Anyway, Geodon (ziprasidone) is an interesting candidate for augmenting SSRI-therapy in a low dose - perhaps less than 20mg would already be enough? At such a dose, the whole cascade of the drug's other actions would hardly yet be put into motion. An even more interesting candidate, in my opinion, would be sertindole, which is a potent 5HT2A/C-blocker that touches D2 only lightly in comparison. In contrast to Geodon, that has a very short half-life, sertindole has a long half-life and it's blocking effects on 5HT2A are reported to be long-lasting. Sertindole was temporarily withdrawn from the market after reports of sudden death and the like because of its tendency to prolong QT-interval; later studies revealed, however, that this tendency wasn't any greater than that of most other AAP's; Risperdal, for instance, is a worse offender when it comes to QT-interval-prolonging. Anyhow, the QT-interval-prolonging is dose related, and I think that even a 4mg dose (therapeutic dosage for schizofrenia is >20mg) would be enough for the goal I have in mind. Sertindole, sadly, is considered a second-line treatment and hasn't even been investigated, it seems, as an augmentation strategy for SSRI-treatment. So who will ever prescribe it for me?! Then you have the good ol' TCA's, of course, most of which throw in a bit of 5HT2A or -C antagonism among all the other stuff they're doing. You can see and compare their 5HT2A-antagonistic properties in this table: http://www3.interscience.wiley.com/cgi-bin/fulltext/121665024/main.html,ftx_abs#t3 When you remember the (A)AP-table, you will realize that the 5HT2A or -C antagonism of the TCA's is rather weak and will probably only come into full play at therapeutic rather than low doses. That's a pity, because at such doses the side-effects of TCA's are so severe that only the truly heroic stand their ground. Which leaves the rest tantalized. Amitriptyline, for instance, has perhaps the best ratio of SRI versus NRI versus 5HT2A (and -C)-blockade. But it's a stronger antihistaminergic than Zyprexa (see there), and it's a very strong anticholinergic, and a very dirty drug overall, so though certainly undeserved, it IS imaginable that some doctor's have called the drug 'rat poison'. To draw towards the end. My personal suggestion (towards myself, that is) for a fine antidepressant cocktail with both anxiolytic and stimulating and motivating qualities would be: sertraline (Zoloft) + sertindole or ziprasidone (Geodon) or, if those aren't available, Risperdal + Buspar (buspirone), the 5HT1A-agonist. On paper, it looks good. What do you think?

Trazodone or Remeron <-- both are POTENT 5-HT2A antagonists, only Remeron has affinity for 2C.


I think you are correct you insightful poster. Good to see kids are still learning!
Now to dig a little further.
The research on autoreceptors.

Dopamine auto-receptors, that is.




                                     Eur J Neurosci. 2008 Oct;28(8):1480-90. doi: 10.1111/j.1460-9568.2008.06450.x. 

Chronic activation of the D2 dopamine autoreceptor inhibits synaptogenesis in mesencephalic dopaminergic neurons in vitro.

Fasano C1, Poirier A, DesGroseillers L, Trudeau LE.

 Abstract

Chronic blockade or activation of dopamine receptors is critical for the pharmacological treatment of diseases like schizophrenia, Parkinson's or attention deficit and hyperactivity disorder. However, the long-term impact of such treatments on dopamine neurons is unclear. Chronic blockade of the dopamine D2 receptor in vivo triggers an increase in the axonal arborization of dopamine neurons [European Journal of Neuroscience, 2002, 16, 787-794]. However, the specific involvement of presynaptic (autoreceptors) vs. postsynaptic D2 receptors as well as the molecular mechanisms involved have not been determined. Here, we examined the role of D2 autoreceptors in regulating the ability of mouse dopamine neurons to establish axon terminals. Chronic activation of this receptor with quinpirole, a specific agonist, decreased the number of axon terminals established by isolated dopamine neurons. This effect was accompanied by a decrease in dopamine release and was mediated through inhibition of protein kinase A. The decrease in axon terminal number induced by D2 receptor activation was also occluded when the mammalian Target of Rapamycin pathway of mRNA translation was blocked. Our results suggest that chronic activation of the D2 autoreceptor inhibits synaptogenesis by mesencephalic dopamine neurons through translational regulation of the synthesis of proteins required for synapse formation. This study provides a better understanding of the impact of long-term pharmacological interventions acting through the D2 receptor.

PMID: 18973573 [PubMed - indexed for MEDLINE]

What does this all mean...?
Well basically autoreceptors are the brain's own receptor based negative feedback system for dopamine; telling the brain "we are having too much dopamine activation, let's decrease and / or moderate the release of by this receptor). It's a built in wiring "insurance policy" ensuring that dopamine increases will always be associated or followed by a decrease.

______________________________________________________________

__________________________________________________________________________

Point is. Dopamine D2 has two receptor subtypes, pre-synaptic D(2) Short (S) - "D2S" - receptors which INHIBIT dopamine - and Dopamine D(2) Long - "D2L" which activate their own actions. 

In light of this - there aren't many compounds that actually block dopamine auto-receptors besides Amisulpride, and only at lower doses, at higher doses it acts as an AntiPsychotic drug and blocks them all. Point being - Dopamine D2 has two receptor subtypes, pre-synaptic D(2) Short (S) - "D2S" - receptors which INHIBIT dopamine - and Dopamine D(2) Long - "D2L". Blocking ONLY D2S's - due to the fact that there aren't many compounds AVAILABLE - you would certainly need to experiment with low dose Amisulpride. However there are "pathways" that need to be ensured before we even get to that.


Also - IN ORDER TO UNDERSTAND DOPAMINE PRODUCTION AND FEEDBACK - we need to understand the CENTRAL MECHANISM and following effects of D(2) like RECEPTORS. 

SPECIFICALLY, Dopamine D(2) receptors INHIBIT adenlyl cyclase - which then INHIBITS - CYCLIC ADENOSINE MONOPHOSPHATE (cAMP) - which then the decrease of this (since cAMP normally stimulates the Enzyme TYROSINE HYDROYXLASE) decreases TYROSINE hydroxylase ; the enzyme by which dopamine is produced from the amino acid TYROSINE. Cyclic AMP is positively correlated with Protein Kinase A activation.

Thus - CYCLIC AMP is KEY to activating dopamine activity, and since Cyclc AMP is related to THYROID function, there is a STRONG link between associated thyroid hormones (such as T4 and T3) and dopamine synthesis.

Brain Res. 1988 Jul 26;456(2):302-9.

Evidence that adenosine A2 and dopamine autoreceptors antagonistically regulate tyrosine hydroxylase activity in rat striatal synaptosomes.

Onali P1, Olianas MC, Bunse B.

Abstract

Incubation of rat striatal synaptosomes with the adenosine receptor agonist 2-chloroadenosine (2-CADO) produced a concentration-dependent increase of dopamine (DA) synthesis (about 50% of control value). The effect was not additive with the stimulation produced by either 10 microM forskolin or 2 mM dibutyryl cyclic AMP. Pretreatment of striatal synaptosomes with 2-CADO produced an activation of tyrosine hydroxylase (TH) which withstood washing and lysing of the tissue. This activation was largely independent of the presence of Ca2+ ion in the preincubation medium and, when analyzed as a function of different concentrations of the pterin cofactor 6-methyl-5,6,7,8-tetrahydropterin (0.08-0.4 mM), it was associated with an apparent increase in the Vmax of the enzyme. Quinpirole, a selective D2 DA receptor agonist, reduced control synaptosomal DA synthesis and caused a persistent inhibition of TH activity. When added together with 2-CADO, quinpirole depressed the stimulation of DA synthesis and TH activity produced by the adenosine analog. The effect of quinpirole was stereospecifically antagonized by the D2 DA antagonist sulpiride. Quinpirole also inhibited the activation of TH elicited by a submaximal concentration of forskolin, but not that produced by dibutyryl cyclic AMP. The inhibitory effect of quinpirole on basal and 2-CADO-stimulated TH activities was mimicked by DA. These results indicate that presynaptic DA autoreceptors and adenosine A2 receptors interact antagonistically in controlling DA synthesis in rat striatal synaptosomes presumably by exerting opposite inputs on a presynaptic adenylate cyclase system.PMID: 2905190 [PubMed - indexed for MEDLINE]

Now there are many ways to increase Cyclic AMP.

One of those is by supplementing with a compound called "Forskolin" - a direct adenylyl cyclase ACTIVATOR. As one of the supplements that activate adenylyl cyclase - we will expect as seen above, an INCREASE in cyclic AMP. Now we have more tyrosine hydroxylase - and thus more DOPAMINE.

As another big note ::: None of this will apply if you aren't getting the necessary amino acids in your diet!!!! 
Therefore, if you attempt to apply any information in this article, remember that PROTEIN intake is ESSENTIAL! I suggest eating a handfull of peanuts and getting the rest of your protein from lean meat.


Let's review so far.

Methods of increasing dopamine activity.

• Blocking/Antagonizing 5-HT2A / 2C receptor activity.
• Blocking auto-receptors using low - dose amisulpride.
• Increasing Protein Intake
• Supplementing with Forskolin.

The next one is kinda like hitting two birds and a squirrel with one jagged stone.

YOHIMBINE

Why Yohimbine...?

For good reason - it blocks many serotonin receptor subtypes that have detrimental effects on dopamine synthesis and also cause vasoconstriction. Some of these are the serotonin 5-H1(B) receptor, 5-HT1(D) receptor and 5-HT2(B) receptor. That means that by blocking serotonin's effect on these receptors, Yohimbine allows for both vasodilation and dopamine release.

Second to all of this - Yohimbine blocks Central Alpha-2-receptor's VERY POTENTLY.

By blocking Alpha-2-Receptors, dopamine release is enhanced.

So just with the triple triple cocktail of Yohimbine, Trazodone (or Remeron) and Forskolin we have a super boost in dopamine. Add in ami sulpride at very low dose - and we've enhanced it even more.


Now let's move to other aspects of dopamine's breakdown.

MONOAMINE OXIDASE ACTIVITY

Monoamine Oxidase type A - is an enzyme that breaks down Catecholamines/Monoamine's; dopamine, epinephrine, norepinephrine and serotonin. Monoamine Oxidase also has a type B ; and this breaks down Dopamine and Phenylethylamine ONLY.

To maximize dopamine, both of these enzymes should be inhibited.

However, we are starting to cross the red river here as far as side-effects.
Always keep an alpha-blocker on hand, no-one should be applying any of these concepts without having an anti-nausea/sympatholytic drug on hand.

VERY IMPORTANT : Wiping out MAO-A and MAO-B does NOT require drugs AT ALL. 
They are ANTIOXIDANT based enzymes, the more antioxidants you have in your blood, the less of these enzymes that break down dopamine and EPI etc.


To inhibit MAO-A and MAO-B ...you only need two products.
Syrian RUE and KAVA KAVA.

Syrian Rue can be found here ---> Herbs of the Gods
KAVA KAVA can be found ---> HERE

Syrian Rue (Peganum Harmala) extract 10x

NEXT ASPECT OF DOPAMINE BREAKDOWN...

DAT (Dopamine Transporter)

To inhibit this transporter which will then allow for more dopamine to stay active (and not get used up quickly) - we need transporter inhibitors (specifically DAT and NET inhibitors).

NET is norepinephrine transporter...why inhibit this? Because dopamine is INACTIVATED by NET in certain area's of the brain...very important area's in cognitive processing and emotions such as Prefrontal Cortex. So to REALLY maximize dopamine...we would have to block both DAT and NET...which locks both dopamine and norepinephrine into the synapse. ALWAYS KEEP AN ALPHA BLOCKER ON HAND. So you don't get high BP....you should be only the HEALTHIEST of an individual to try these methods out. 

To inhibit both DAT and NET...

We only need one or two HERBS.

1.) CATUABA Extract

2.) Kava Kava Extract.

Kava inhibits both NET and MAO-B, while Catuaba inhibits DAT.

Now with all the methods listed so far.

We only have ONE method left..one little trick left in maximizing dopamine to absolutely SUPRAPHYSIOLOGICAL concentrations.

A transporter called "VMAT".

VMAT is what Amphetamines bind to. But we don't need amphetamines.

We only need one substance. The natural form of amphetamine already present in our body.

PEA - Phenylethylamine. If we take this orally, while inhibiting MAO-B...then we have already done our deal with the devil..because MAO-B inhibition ensures PEA stays around...which means we ENSURE VMAT Inhibition!


There is one little feeback mechanism NOT mentioned yet...


NMDA-receptors. When you interfere with NMDA glutamate receptors, you will actually indirectly block the reuptake of dopamine, leading to enhanced dopamine Activity.