Dopamine receptor ^ûp^ modulation

[c0rt3x]

Good evening dear hopefully highly honored open minded people. =)



Yesterday I had some as sudden as inspirational insights:


Stimulants of the future will almost by guarantee be: The for some very strange reason seemingly completely overseen category of ...

...Dopamine Receptor Up Modulators.


(
GABA Receptor Down Modulators: Flumazenil
GABA Receptor Up Modulators: Diazepame, Lorazepam


Dopamine Receptor Down Modulators: Olanzapine, Quetiapine
Dopamine Receptor Up Modulators: ?!
)

So remember my words when you will find yourself DRUMing in the near future.


I could now spend some time on argumenting why this is so very possible - but I'd say that it takes no more than this litle hint in order to litterally proove that:

DRUMs rock!


Cheers!

 

[rickolasnice]

Is modulator a real term or do you mean regulator? If so you have the chemicals the wrong way round for what they do.. and it would simply not work as increasing dopamine in the synapse = stimulants affects.. this will inevitably cause some down regulation of dopamine receptors..

 

[sekio]

The term you are looking for is a positive allosteric modulator. Lorazepam and the other benzodiazpines bind to the benzodiazepine binding site on the GABA-A receptor and increase the likelihood that it will open when GABA binds. Flumazenil and other anti-benzo drugs are conversely negative allosteric modulators.

I don't think the dopamine receptors have a PAM site the same way that the GABA receptors do. Olanzapine and quietapine actually act as antagonists (that is, when they attach to the receptor they block effects or produce an opposite effect from the "normal" chemical) rather than "down regulators" or negative allosteric modulators.

 

[vecktor]

it is not easy to compare GABA receptor which is an ionotropic receptor with the Dopamine receptor in all its flavours which is a metabotropic receptor, they work in radically different ways.

there are already catcholamine activity enhancers which do a similar thing but cause greater neurotransmitter release when stimulated, things like BPAP and PPAP neither of which is regarded as fun.

 

[Sturnam]

The term you are looking for is a positive allosteric modulator.

Thanks for that. I literally had no idea what this guy was talking about. I thought he was talking about increasing dopamine receptor expression, not allosteric modulators.

I don't think the dopamine receptors have a PAM site the same way that the GABA receptors do.

I don't see why they couldn't though. I'd say it's definitely possible that there's some binding site that can make activation more/less likely.

 

[nj754]

I read this article in Scientific American a couple years ago which made allosteric modulators sound like a promising area for new drug discovery.

http://www.scientificamerican.com/article.cfm?id=a-biochemical-way-to-reduce

I don't think it would necessarily have to act on dopamine receptors. There may be some specific subtype of glutamate receptor, for instance, that would do the same thing. These allosteric drugs can be highly specific in what receptor they hit.

The fact that we (apparently) don't know of any drugs that do this, though, seems like a bad sign. Benzodiazepines were discovered by accident, not by some targeted effort to look for allosteric GABA modulators. If there were allosteric recreational drugs out there to be found, there is at least a decent chance that we would already have a few examples.

 

[Wizzle]

Isn't this what happens when you take NMDAR-antagonists?

 

[c0rt3x]

The term you are looking for is a positive allosteric modulator.

Thank you for this correction!

I don't think the dopamine receptors have a PAM site the same way that the GABA receptors do. Olanzapine and quietapine actually act as antagonists (that is, when they attach to the receptor they block effects or produce an opposite effect from the "normal" chemical) rather than "down regulators" or negative allosteric modulators.

Why are Olanzapine and Quetiapine then classified as atypical neuroleptics?


PS:

I've just found this:

"Dopamine activity enhancers such as BPAP and PPAP, which are currently only research chemicals, but are being investigated for clinical development in the treatment of a number of medical disorders."


BPAP:

"(-)-1-(Benzofuran-2-yl)-2-propylaminopentane ((-)-BPAP) 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.[1][2]

BPAP (along with another similar compound PPAP) is classified as a catecholaminergic and serotonergic activity enhancer. This means that it stimulates the impulse propagation mediated transmitter release of the neurotransmitters dopamine, norepinephrine and serotonin in the brain. However, unlike stimulant drugs like amphetamines, 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 amphetamines and BPAP increase the amount of neurotransmitters that get released, amphetamines cause 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.[3][4]

Other drugs which produce this effect are the endogenous trace amines phenethylamine and tryptamine, and the neuroprotective MAO-B inhibitor selegiline.[5] 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.[6]"

http://en.wikipedia.org/wiki/%28-%29-1-%28benzofuran-2-yl%29-2-propylaminopentane


---> It seems like "(Dopamine) Activity Enhancers" (DAE) are indeed currently researched. :D

Has anyone seen DAE-RCs yet?

 

[sekio]

BPAP had a bit of a fiasco surrounding it regarding it being a benzofuran and possible liver destruction. AFAIK there are no dopamine activity enhancers on the open market.

Like most atypical antipsychotics, compared to the older typical ones, olanzapine has a lower affinity for histamine, cholinergic muscarinic and alpha adrenergic receptors.

I think the whole "typical"/"atypical" labeling is dumb. Usually the only difference between the 2 is selectivity over other targets.

 

[Nagelfar]

Stimulant's positive reinforcing effects may have nothing even to do with monoamine levels & agonism directly, take for example the possibility of their function similar to the neuropeptide CART ("Cocaine and amphetamine regulated transcript").

 

[nj754]

After a few quick web searches on BPAP, I still can't tell what receptors it actually targets and how. I don't think we can assume that it's an allosteric modulator. Mirtazapine has been called an enhancer and a lot of similar things, but it's actually a simple antagonist at pre-synaptic monoamine autoreceptors and heteroreceptors.

 

[vecktor]

After a few quick web searches on BPAP, I still can't tell what receptors it actually targets and how. I don't think we can assume that it's an allosteric modulator. Mirtazapine has been called an enhancer and a lot of similar things, but it's actually a simple antagonist at pre-synaptic monoamine autoreceptors and heteroreceptors.

bpap and ppap are clearly NOT an allosteric modulator at monoamine receptors, they were mentioned because their MO is similar to the hypothetical dopamine receptor up regulators and tel us that it is not likely to be fun.

 

[retard]

Cardio exercise sensitizes dopamine
Nmda antagonist can upregulate D2/ D3
Nicotine

Dopamine

Dopamine neurons in the ventral tegmental area and the substantia nigra have nAChr's (particularly the alpha4beta2 and alpha3beta2 subunits) located on their nerve terminal membranes; when these receptors are stimulated, dopamine is secreted (7,8,9,10). Nicotine-evoked glutamate release can enhance such secretion due to the presence of NMDA receptors on the dopamine terminals (11, 12). However, despite such robust dopamine release, overflow of dopamine in areas of the brain like the nucleus accumbens is tightly controlled by the dopamine re-uptake system (13).

In order to overcome such an effect, a dopamine re-uptake inhibitor might prove very useful in potentiating nicotine's dopaminergic action. But even without a re-uptake inhibitor, chronic use of nicotine by itself can increase dopamine overflow (14), and it is the NMDA receptors that are at least somewhat responsible for this sensitization mechanism (15). Another sensitization mechanism could be induced via nicotine's upregulation of D1, D2, and D3 receptor mRNA (16,17).

A third mechanism by which dopamine release is sensitized by chronic nicotine treatment is through increased tyrosine hydoxylase expression. Nicotine increases tyrosine hydroxylase mRNA in the brain, as well as the actual tyrosine hydroxylase protein (18). Since tyrosine hydroxylase is the limiting factor in the conversion of L-tyrosine to dopamine, nicotine should result in increased synthesis of dopamine, assuming that L-tyrosine intake is adequate. And indeed, when L-tyrosine and nicotine are administered together in-vitro to human lymphocytes, synthesis of L-Dopa and norepinephrine commences. (19)

Monoamine Oxidase type B (MAO-B) is one of the enzymes responsible for degrading dopamine. It's been known for some time that cigarette smoke has the capability of irreversibly inhibiting MAO-B (20). And while nicotine metabolite concentration is inversely proportional to MAO-B levels, nicotine itself does not inhibit MAO-B (21). Inhibition of MAO-B compounded by nicotine's effects on dopamine release is probably one of the primary reasons why cigarettes are so rewarding and might add to their effect on body composition. In order to potentiate nicotine's dopaminergic action without smoking, one could take the MAO-B inhibitor l-deprenyl. Also, since l-deprenyl has dopamine re-uptake blocking activity (22), it would provide a double mechanism for making nicotine's effect on dopamine more pronounced.

http://www.snuson.com/forum/archive/index.php/t-9055.html

 

[nj754]

^^^ Maybe that explains why I hate cigarettes alone, but I like them when combined with opioids.

The fact that DA neurons in the VTA have both nicotinic ACh receptors and NMDA receptors argues in favor of the point I made in #6 above, which is that a pleasurable drug need not necessarily target DA receptors directly. So, even if there is no site for a positive allosteric modulator on DA receptors, there could be one on nACh receptors or NMDA receptors on the same neurons.