7 replies to this topic

[Intropersona]

Specifically with regard to NMDA receptor antagonists such as discosciative laughing gas...

Could antagonism lead to better sensitivity for racetam functioning?

[Tom_]

Unless you use it repeatedly often before the half life is over its unlikely. For example 6 weeks of memantine would be expected to cause an increase in receptor density and sensitivity.

[Intropersona]

Unless you use it repeatedly often before the half life is over its unlikely. For example 6 weeks of memantine would be expected to cause an increase in receptor density and sensitivity.

Half life, ok thanks. Isn't there a difference between a partial antagonist like Memantine and a strong antagonist that causes full blown depersonalisation?

[Intropersona]

Can someone please verify this is true? Nitrous oxide increases memory by altering NMDA receptor density?

[medicineman]

antagonists will usually cause upregulation. Block a receptor from being activated, and cascades of reactions will take place to increase receptor density. A good example is beta blockers. This is exactly the reason behind the idea of tapering off them rather than abrupt withdrawal, as given sufficient time and blockade, a large increase in receptor density will precipitate a massive catecholaminergic response, and consequential ischemia and heart attacks (which are pretty hard to treat relative to typical atherosclerotic/thrombotic ischemic events)

Specific to NMDA, yes blockade will cause upregulation. This is the rationale for alcohol withdrawal following chronic alcoholism. Alcohol is a potent NMDA antagonist, and abrupt withdrawal likely precipitates chaos at these receptor sites.

Memantine is a bit different, in that it is low affinity and voltage dependent. I think, this makes it unlikely to cause major changes to receptor densities, since it will not constantly and consistently block the receptors. (low voltage, low affinity, makes it similar to magnesium, but with higher affinity)

Edited by medicineman, 10 July 2014 - 12:33 PM.

[Intropersona]

antagonists will usually cause upregulation. Block a receptor from being activated, and cascades of reactions will take place to increase receptor density. A good example is beta blockers. This is exactly the reason behind the idea of tapering off them rather than abrupt withdrawal, as given sufficient time and blockade, a large increase in receptor density will precipitate a massive catecholaminergic response, and consequential ischemia and heart attacks (which are pretty hard to treat relative to typical atherosclerotic/thrombotic ischemic events)

Specific to NMDA, yes blockade will cause upregulation. This is the rationale for alcohol withdrawal following chronic alcoholism. Alcohol is a potent NMDA antagonist, and abrupt withdrawal likely precipitates chaos at these receptor sites.

Memantine is a bit different, in that it is low affinity and voltage dependent. I think, this makes it unlikely to cause major changes to receptor densities, since it will not constantly and consistently block the receptors. (low voltage, low affinity, makes it similar to magnesium, but with higher affinity)

 

Thanks for replying,

 

When you say "Abrupt withdrawal likely precipitates Chaos" do you think that could go for intense (slightly voltage dependent) antagonists like Nitrous Oxide, Ketamine, Dextromethorphan, PCP? What would be symptoms of this "Chaos"?

 

I assumed an increase in receptor density meant more receptors exchanging neurotransmitters and therefore leading to neurons firing more often and therefor stronger plasticity. This is not the case though?

[medicineman]

antagonists will usually cause upregulation. Block a receptor from being activated, and cascades of reactions will take place to increase receptor density. A good example is beta blockers. This is exactly the reason behind the idea of tapering off them rather than abrupt withdrawal, as given sufficient time and blockade, a large increase in receptor density will precipitate a massive catecholaminergic response, and consequential ischemia and heart attacks (which are pretty hard to treat relative to typical atherosclerotic/thrombotic ischemic events)

Specific to NMDA, yes blockade will cause upregulation. This is the rationale for alcohol withdrawal following chronic alcoholism. Alcohol is a potent NMDA antagonist, and abrupt withdrawal likely precipitates chaos at these receptor sites.

Memantine is a bit different, in that it is low affinity and voltage dependent. I think, this makes it unlikely to cause major changes to receptor densities, since it will not constantly and consistently block the receptors. (low voltage, low affinity, makes it similar to magnesium, but with higher affinity)

 
Thanks for replying,
 
When you say "Abrupt withdrawal likely precipitates Chaos" do you think that could go for intense (slightly voltage dependent) antagonists like Nitrous Oxide, Ketamine, Dextromethorphan, PCP? What would be symptoms of this "Chaos"?
 
I assumed an increase in receptor density meant more receptors exchanging neurotransmitters and therefore leading to neurons firing more often and therefor stronger plasticity. This is not the case though?

An increase in receptor density can both be desirable and undesirable. Opiate withdrawal being a classic example of an undesirable effect of increased receptor density without the supraphysiological stimulation. There are also complex cascades which increase the effect of the ligand itself (efficacy) to its receptor site. Insulin acting as an indirect inotrope via alterations in arrestin levels thus making adrenergic receptors more responsive to endogenous ligands etc. is an example of how efficacy itself maybe enhanced.
Upregulation of trkB receptor via telmisartan, for example, is possibly why hypertensives on the drug are less likely to develop dementia.

Memantine is a low affinity uncompetitive antagonist therefore it is less likely to cause any unwanted effects, since it's property of being voltage gated with low affinity, makes it work when the conditions are just right, hence it doesn't constantly and consistently block it's receptor.

Ketamine, pcp, etc are voltage independent and uncompetitive, hence they block, no matter what amount of endogenous agonist you have, and no matter what the conditions are. There is plenty of literature pointing out the rapid compensatory upregulation of nmda receptors following administration of ketamine. This can be desirable, since nmda receptors are implicated in memory and bdnf, but it's a double edged sword, as this could tip the balance towards excitotoxicity, as nmda receptor overactivity is implicated in many neurodegenerative diseases.

My statement regarding chaos at the receptor site, I am referring to hypersensitivity and increased receptor densities of nmdars. This is the pathological basis of alcohol withdrawal, especially delirium tremens. We know now that alcohol withdrawal is a result of increased and hyperexcited nmdars causing significant cytotoxicity.

I'm not sure about the other ligands you mention, but I'm sure from what I have written, you can through a little bit of searching, find the information you need.

I hope I am answering your question. At least I think I am

Edited by medicineman, 10 July 2014 - 08:31 PM.

[Major Legend]

I think this topic is extremely interesting and not discussed enough, frankly downregulation is IMO the BIGGEST problem with chemical enhancements for humans at the moment.

 

Another interesting problem is the running out of precursor reactions (e.g. lack of dopamine production) leading to a period of relapse between effective properties, these reactions are usually heavily rate controlled which make them hard to manipulate.

 

Some interesting questions to me:

 

Is the tolerance mechanism different for each chemical or are they all relatively similiar?

 

What kind of ways can we reverse them? Antagonists should cause upregulation, but it doesn't seem they are always needed for upregulation, also antagonists are likely to cause the opposite of what you desired in the first place. e,g, memantine makes you stupid by going the opposite route of the system.

 

I am surprised not more people are asking the counter route for most drugs, since most here are probably considering healthy long term use rather than "getting high"