Differences between agonists, releasers, precursors & reuptake inhibitors

[ribbit]

Hey Bluelight, I have some basic to advanced questions regarding the way different forms of increasing neurotransmitter release affect the body. So far I think I have a basic understanding that a:

1 - a direct agonist will mimic the neurotransmitter and cause a release similar to said neurotransmitter while displacing the neurotransmitter from the (neuron?) and depending on its affinity can be displaced by other agonists or antagonists?

2 - a releaser will cause the release of the neurotransmitter and trigger the effects that occur when said neurotransmitter is fired.

3 - a precursor will cause an over abundance of the neurotransmitter which in effect will encourage release but more so just serves as fuel one could say, waiting to be utilized

4 - a reuptake inhibitor will keep the neurotransmitter hanging around in the part of the brain where said neurotransmitter performs its actions, when reuptake inhibition wears off, the neurotransmitters are subject to destruction via MAO? Also, reuptake inhibitors have the effect of encouraging release of said neurotransmitter?

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This is my basic understanding on these functions, if I am incorrect please enlighten me.

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Now here are my actual questions:

5 - Each of these effects seems to cause a tolerance, however I am under the impression that tolerance to each only overlaps so much, and if one were to cycle correctly, one could avoid or at least minimize tolerance by alternating ones drug of choice. If this theory is correct, what would be the optimal way to alternate? Specifically, which methods cause the most and least tolerance, as well as which methods overlap in terms of tolerance?

6 - Mixing different drugs with different actions is a common way to potentate, but also can diminish effects depending on the combination. If we are speaking with pure releasers, agonists, reuptake inhibitors, and precursors, which combinations would cause the strongest effects, and which combinations would null each others effects? I have some guesses but I really would appreciate the guidance of a more experienced mind.

7 - I am pretty sure I know the answer to this last one, but I feel like I should ask it regardless. (This is referring to long term use and long term effects, not immediate.) Taking an abundance of 5-htp will eventually cause a decrease of dopamine, however if one takes a serotonin releaser, would this eventually cause a proportional abundance of serotonin? Or would the effect be opposite, seeing how all the serotonin has been used and now the dopamine is the majority?

8 - Do agonists cause a depletion of neurotransmitters? Do they cause down-regulation of the receptor that receives the agonis? Do they also cause down-regulation for the receiving of the actual neurotransmitter as well?

Thank you so much, I apologize for my lack of formal education and feel fortunate to be around such brilliant minds that can assist my quest!

 

[sekio]

Direct agonist = chemical that makes a certain subtype or subtype(s) of receptor protiens change conformation and become 'active'. Examples include dopamine (D1-D5 dopamine receptors), THC (CB1/2 cannabinoid receptors), LSD (5-HT receptors, dopamine receptors).

Only in certain cases does direct receptor activation actually cause release of neurotransmitters. Ususally that is when you have a drug that primarily has an effect at autoreceptors - or receptors meant to sense the level of a neurotransmitter. In that case, agonism will result in your body releasing less nt, and antagonism will cause your body to think there is less n/t and release more. An example of an autoreceptor is the alpha-2a adrenergic receptor. (yohimbine = antagonist, clonidine = agonist)

Reuptake inhibitor = Binds to a protien known as a 'transporter' that normally returns a neurotransmitter to a part of the neuron known as a vesicle. Drugs of this class raise neurotransmitter levels with acute treatmkent but cause long-term receptor downregulation & tolerance as your body becomes accustomed to high n/t levels.

Most dopamine/norepinephrine reuptake inhibitors that bind quickly are considered recreational (cocaine, methylphenidate). Serotonin reuptake inhibiton on its own is not considered 'fun' per se.
Generally reuptake inhibitors do not cause or increase direct release of monoamines.

Neurotransmitter precursors = chemicals your body uses to create neurotransmitters. Unless you take these in large doses or you have a genetic problem, your body produces as much as it needs from dietary protien.
There is evidence that taking large doses of precursors like L-DOPA or 5-HTP may actually be harmful so I don't suggest mucking with them.

Releasing agent = chemicals that bind to transporter protiens and 'reverse' their actions. Classic examples are amphetamine, methamphetamine, MDMA. These cause the vesicles to empty into the synapse and cause relatively large spikes in n/t release. Almost always considered euphoric. Stronger releasers are considered neurotoxic (4-chloroamphetamine, meth).
Some of these also block MAO.

MAO is always processing neurotransmitters. It is the main method that n/t's are degraded by. If it didn't act then you would have a serious problem & go into hypertensive crises if you e.g ate cheese.

Each of these effects seems to cause a tolerance, however I am under the impression that tolerance to each only overlaps so much, and if one were to cycle correctly, one could avoid or at least minimize tolerance by alternating ones drug of choice.

Nope, this is bullcrap. What actually produces tolerance is the receptor agonism. The other 2 classes of drugs are just indirect ways of causing more n/t's to act in your brain. That said, usually full agonists and releasing agents will produce tolerance the fastest, with partial agonists and reuptake inhibitors taking more time to produce tolerance.

6. In general, the rule-of thumb is that the drug with the highest affinity wins. The case of reuptake inhibitors vs releasers is a strange one because sometimes a reuptake inhibitor will block a releasing agent from working. (SSRI vs MDMA, methylphenidate vs amphetamine).

7. No, I think you need to read pubmed some more because this question makes no sense.

8. No, yes, yes. Receptor down-regulation is a property inherent to the receptor subtype, not to the drug that binds... for instance CB1r does not have a seperate 'JWH-tolerance' and 'THC-tolerance', they are both one...

 

[ribbit]

Thank you for the quick and thorough response

 

[5000m]

great thread!

 

[sir_thizzalot]

All I'll comment on is 5.
This is true to some extent. But, if you have a low DA level, you'll have some tolerance to all these different kinds of drugs. That being said, I basically did what you're saying here (really mix up what drugs you're doing, doing ones that work different ways on DA), thinking it'd be smart so I wouldn't get addicted to any one... It sort of worked, I guess, but you need to keep in mind that if you're doing all these drugs, you'll be risking DA receptor down regulation, as you probably WILL be able to get higher, more often, and with various enjoyable effects since very few if any drugs work only on DA, which sounds great at first glance...

 

[_Olon_]

A way to overcome tolerance by agonist is changing gene regulation to upregulate the desired receptor. Examples: acetyl-L-carnitine or the HDAC inhibitor SAHA for mGlu2 receptors, the HDAC inhibitor sodium butyrate for 5-ht1a receptors. Histone deacetylase inhibitors not only inhibit the deacetylation of histones (the DNA packing molecules), but also the deacetylation of transcription factors. There is a large number of HDAC subtypes, so that different HDAC inhibitors will increase the expression of different genes. Currently a number of subtype specific HDAC inhibitors is developed and tested.

 

[Nagelfar]

Are auto-receptors different in structure from the usual receptors responsible for agonist efficacy? If so could an agonist be made to have less affinity for auto-receptors, or are they usually identical to the other receptors for the same class of agonist?

 

[sekio]

Autoreceptors, to my knowledge, are generally distinct subtypes of G-protien receptors. To the best of my knowledge, 5-HT1a and alpha-2a adrenergic are both autoreceptors in some areas of the brain.

I guess it depends on the particular system... alpha-2a is really what I think of when I see the word autoreceptor. Clonidine, an agonist, greatly suppreses adrenaline/NE release. Yohimbine, antagonist, increases NE/adrenaline release.

 

[Nagelfar]

Am I simplifying the matter to think that an exogenous agonist which works on all receptors except for the auto-receptors, of a particular system, would have a much reduced down-regulation?

 

[sekio]

I think you are.

As far as I know long-term tolerance is based upon the attachment of beta-arrestin & subsequent internalisation of the G protien receptor complex. Autoreceptors only play a major role in the short-term homeostasis of neurotransmitters.

 

[endotropic]

Autoreceptors, to my knowledge, are generally distinct subtypes of G-protien receptors. To the best of my knowledge, 5-HT1a and alpha-2a adrenergic are both autoreceptors in some areas of the brain.

I'd just like to clarify that receptor subtypes which are autoreceptors in some parts of the brain may be regular postsynaptic receptors in others. For example the 5-HT1a receptor is primarily an autoreceptor in the hippocampus but primarily a postsynaptic receptor in the frontal cortex.

Are auto-receptors different in structure from the usual receptors responsible for agonist efficacy? If so could an agonist be made to have less affinity for auto-receptors, or are they usually identical to the other receptors for the same class of agonist?

So despite the fact that autoreceptors and postsynaptic receptors of a specific subtype are structurally identical, there are drugs with efficacy at the autoreceptor (they're agonists) but with no efficacy at the postsynaptic receptor (antagonists) and vice versa. So these drugs are effectively selective for one population of the receptor subtype over another, identical population. Somehow...