Is this a good analogy for the stimulants?

[deadendgame]

Hey guys, I have an analogy I just made up for the stimulants. So dopamine is the neurotransmitter responsible for focus, motivation, euphoria, etc. Stimulants elicit their effect by dopamine reuptake inhibition. Caffeine by indirect adenosine A1 antagonism, ritalin/coke by only dopamine reuptake inhibition, and amphetamine by vesicular dumping, reuptake inhibition, MAO/COMT inhibition. Essentially what the stimulants are doing is "borrowing" the dopamine from the brains' neurons because the postsynaptic receptors will downregulate themselves later making the dopamine less able to elicit their effects. This is a way of the body collecting its payment: withdrawal symptoms. So in a sense, stimulants are a sort of credit card where caffeine is like a secured 500 dollar credit card. Ritalin/coke is like a 2000 credit limit platnium card. Amphetamine is like a home equity loan and taking meth is like taking out a mortgage!! Your own body will collect its payment in the form of withdrawal symptoms and in the case where you are owing too much, death. Is my analogy of stimulants as a form of credit cards accurate?

 

[serotonin2A]

Norepinephrine also makes a substantial contribution to stimulant effects.

I don't really understand why the analogy you proposed would be useful.

The comparisons are arbitrary and they don't really make the pharmacology easier to understand. Stimulants don't "borrow" transmitters from terminals -- a better analogy with amphetamine would be poking holes in the bottom of a water bottle so that the water leaks out. But even that would be silly because it doesn't really accurately reflect the pharmacology.

 

[JohnBoy2000]

On that general topic:

Dopamine is considered the activating neurochemical in amphetamines....

Dopamine release?

Cause in anti-psychotics, the primary mode of action seems to be dopamine receptor subtype antagonism or inverse agonism.
And of course they're sedating.

Then the anti-parkinsons agents like pramipexole - also sedating (for me, even 0.088 mg, the lowest possible dose, fatigued me terrribly until it wore off.

But then modafinil is a DAT inhibitor, like ritalin - but is considered a stimulant.

My personal experience was effexor was that when raised to 300mg, it became sedating, where 225 was activating, and 150 was sedating.
225, noradrenalne kicks in.
300, dopamine kicks in.
Though the sedation could have been attributable to the excess of serotonin at that high dose, which also makes me drowsy (high dose lexapro).

And most recently, bupropion at 450 mg - the dose at which it begins to act as a DRI - also terribly sedating.


So - is dopamine normally considered an activating neurochemical - as it's so often referred to as the "reward, motivation" chemical.

Or sedating??

 

[serotonin2A]

On that general topic:

Dopamine is considered the activating neurochemical in amphetamines....

Dopamine release?

Cause in anti-psychotics, the primary mode of action seems to be dopamine receptor subtype antagonism or inverse agonism.
And of course they're sedating.

Then the anti-parkinsons agents like pramipexole - also sedating (for me, even 0.088 mg, the lowest possible dose, fatigued me terrribly until it wore off.

But then modafinil is a DAT inhibitor, like ritalin - but is considered a stimulant.

My personal experience was effexor was that when raised to 300mg, it became sedating, where 225 was activating, and 150 was sedating.
225, noradrenalne kicks in.
300, dopamine kicks in.
Though the sedation could have been attributable to the excess of serotonin at that high dose, which also makes me drowsy (high dose lexapro).

And most recently, bupropion at 450 mg - the dose at which it begins to act as a DRI - also terribly sedating.


So - is dopamine normally considered an activating neurochemical - as it's so often referred to as the "reward, motivation" chemical.

Or sedating??

Dopamine is involved in reinforcement, motivation, craving, and alertness. A good portion of the stimulant effects of amphetamine are also caused by norepinephrine release.

One issue with D2 agonists is that they can activate dopamine autoreceptors, which would inhibit dopaminergic neuron firing, resulting in feelings of sedation. That isn't a problem in Parkinson's patients because they don't have many dopamine autoreceptors left. The same problems can happen with NET inhibitors because at some doses you get a lot of alpha2 activation, which can induce sedation (alpha2 is a terminal autoreceptor and inhibits NE release). Since the response to an uptake inhibitor is dependent on impulse flow, at certain doses uptake inhibitors can shut down transmitter release.

 

[Nagelfar]

But then modafinil is a DAT inhibitor, like ritalin - but is considered a stimulant.

You say "but" as if qualifying it to be considered something not like the others; ritalin is also a stimulant. However there are modafinil analogs that are sedating

 

[Cotcha Yankinov]

I think modafinil was suspected to have histaminergic actions, and the tuberomammillary nucleus is an important histaminergic wakefulness projection.

 

[Cotcha Yankinov]

That isn't a problem in Parkinson's patients because they don't have many dopamine autoreceptors left.

Is this because because the presynaptic neuron has degenerated or because of adaptive changes?

I remember you've said the efficacy of 5-HT2A antagonism for Parkinson's disease related psychosis/hallucinations is probably due to 5-HT2A sensitization with Parkinson's. Is that because the presynaptic neuron might have degenerated, therefore with less typical axon serotonin release the 5-HT2A are very sensitive to volume transmission?

I suppose with loss of the pre-synaptic SERTs clearing the volume transmission related serotonin there could be more serotonin binding post-synaptically than before when you had pre-synaptic serotonin efflux but also presynaptic SERTs?

 

[serotonin2A]

Is this because because the presynaptic neuron has degenerated or because of adaptive changes?

I remember you've said the efficacy of 5-HT2A antagonism for Parkinson's disease related psychosis/hallucinations is probably due to 5-HT2A sensitization with Parkinson's. Is that because the presynaptic neuron might have degenerated, therefore with less typical axon serotonin release the 5-HT2A are very sensitive to volume transmission?

I suppose with loss of the pre-synaptic SERTs clearing the volume transmission related serotonin there could be more serotonin binding post-synaptically than before when you had pre-synaptic serotonin efflux but also presynaptic SERTs?

Dopaminergic and serotonergic neurons degenerate in Parkinson's disease. Since the autoreceptors are on the dopaminergic cells, there is also a loss of autoreceptors.

Not all serotonergic transmission is volume transmission.

Often, when monoamine transmission is significantly reduced, postsynaptic receptors become supersensitized. That definitely happens with 5-HT2A.

 

[Cotcha Yankinov]

So maybe the (post-synaptic located on non-serotonergic cells) 5-HT2A sensitization is not due to loss of the pre-synaptic cell, but rather the pre-synaptic cell is not getting much stimulation at its dendrites because the cells that synapse onto the dendrites have degenerated, then when an action potential finally comes along the post-synaptic cell goes nuts?

As opposed to the pre-synaptic cell having degenerated and then the sensitized 5-HT2A is just being activated by volume transmission.

 

[serotonin2A]

So maybe the (post-synaptic located on non-serotonergic cells) 5-HT2A sensitization is not due to loss of the pre-synaptic cell, but rather the pre-synaptic cell is not getting much stimulation at its dendrites because the cells that synapse onto the dendrites have degenerated, then when an action potential finally comes along the post-synaptic cell goes nuts?

As opposed to the pre-synaptic cell having degenerated and then the sensitized 5-HT2A is just being activated by volume transmission.

The situation you are describing is not 5-HT2A supersensitivity, but rather an enhancement of dendritic excitability.

5-HT2A receptors exist in membrane bound and cytoplasmic fractions. In the absence of 5-HT2A activation (which would happen if 5-HT neurons die and hence cannot release 5-HT), the cytoplasmic receptors are transported to the cell surface, increasing the number of receptors that can be activated by an agonist.

 

[Nagelfar]

caffeine is like a secured 500 dollar credit card. Ritalin/coke is like a 2000 credit limit platnium card. Amphetamine is like a home equity loan and taking meth is like taking out a mortgage!! Your own body will collect its payment in the form of withdrawal symptoms and in the case where you are owing too much, death. Is my analogy of stimulants as a form of credit cards accurate?

However amp/meth messes up your credit more; studies show amp to be neurotoxic but coke/MPH to be neuroprotective. So if it were a limit platnium card, it'd be one that's use would enhance your credit. (perhaps not credit; perhaps mortgage is just less of a social stigma than simple bankruptcy; which can actually be beneficial to living situation in terms of answering to former debts, lol)

Still, very fatuous analogy

 

[Cotcha Yankinov]

Ohhhh okay, very interesting, thank you.

I guess I was trying to wrap my head around there being a sensitization that is non-linear to the decrease in serotonin available for binding - in other words, if there were 50% more receptors after there was 50% less less serotonin, I was thinking the level of 5-HT2A activation might be similar as before. Although I understand pattern of firing and that sort of stuff probably plays a big role in how messages are communicated, and super sensitized receptors could give rise to differences therein.

But essentially it sounds like once serotonin signaling gets low enough, a process could be set in motion that results in many receptors being brought to the cell surface, and this increase in surface receptors isn't proportional (either in number of receptors or functional response downstream?) to the decrease in serotonin?

Sounds like something that could happen with severe MDMA abuse or severe SSRI withdrawal.

But if we know that 5-HT2A supersensitization is playing a big role in Parkinson's hallucinations, I wonder what supersensitization of other serotonin receptors results in symptomatically (assuming supersensitization of other receptors is possible as it is with 5-HT2A).

 

[serotonin2A]

Ohhhh okay, very interesting, thank you.

I guess I was trying to wrap my head around there being a sensitization that is non-linear to the decrease in serotonin available for binding - in other words, if there were 50% more receptors after there was 50% less less serotonin, I was thinking the level of 5-HT2A activation might be similar as before. Although I understand pattern of firing and that sort of stuff probably plays a big role in how messages are communicated, and super sensitized receptors could give rise to differences therein.

But essentially it sounds like once serotonin signaling gets low enough, a process could be set in motion that results in many receptors being brought to the cell surface, and this increase in surface receptors isn't proportional (either in number of receptors or functional response downstream?) to the decrease in serotonin?

Sounds like something that could happen with severe MDMA abuse or severe SSRI withdrawal.

But if we know that 5-HT2A supersensitization is playing a big role in Parkinson's hallucinations, I wonder what supersensitization of other serotonin receptors results in symptomatically (assuming supersensitization of other receptors is possible as it is with 5-HT2A).

As far as I am aware, the supersensitivity is confined to 5-HT2A. You can't think of the receptors as a group -- each has a different function and a different distribution (both across the brain and within individual cells). 5-HT2A is the major excitatory 5-HT receptor in many brain regions.

What is the reason for your speculation that the 5-HT2A supersensitivity is not proportional to the loss of 5-HT? Is it because the Parkinson's patients have visual hallucinations, which implies a high level of 5-HT2A activation? You have to remember that 5-HT2A receptors are constitutively active, so after a certain point increased 5-HT2A expression would lead to a high level of signaling independent of 5-HT binding. Hence why Acadia was searching for inverse agonists when they developed pimavanserin.

 

[Cotcha Yankinov]

Ohhhhhh, constitutive activity would explain a lot.... Sorry that didn't occur to me. Might one propose that only serotonin receptor subtypes that are constitutively active may have a chance of developing chronic supersensitivity?

Emphasis on chronic, as opposed to more acute supersensitization that might possibly occur with (for example) an acute tryptophan deficit, in which the constitutive activity may not be as necessary for symptomatic effects if there is supersensitization of the receptor in question when the tryptophan deficit is corrected with time and then 5-HT rises sharply. Or is the term supersensitization being used specifically to mean excess constitutive activity, and the aforementioned scenario would just be considered classical upregulation?

You know me, always trying to figure out MDMA abusers issues! It would be interesting if there was sensitization of some receptor subtypes after severe MDMA abuse induced acute 5-HT depletion, and then when the 5-HT rebounds it could cause abberrant neuroplastic changes..

As always, thanks for the insight.

Edit: interesting that 5-HT2A receptors modulate antipsychotic induced dopamine receptor supersensitivity, maybe Pimavanserin is helping with some Parkinson's symptoms that are dopaminergic supersensitivity related as well? https://www.ncbi.nlm.nih.gov/m/pubmed/26508706/

 

[serotonin2A]

Ohhhhhh, constitutive activity would explain a lot.... Sorry that didn't occur to me. Might one propose that only serotonin receptor subtypes that are constitutively active may have a chance of developing chronic supersensitivity?

Emphasis on chronic, as opposed to more acute supersensitization that might possibly occur with (for example) an acute tryptophan deficit, in which the constitutive activity may not be as necessary for symptomatic effects if there is supersensitization of the receptor in question when the tryptophan deficit is corrected with time and then 5-HT rises sharply. Or is the term supersensitization being used specifically to mean excess constitutive activity, and the aforementioned scenario would just be considered classical upregulation?

You know me, always trying to figure out MDMA abusers issues! It would be interesting if there was sensitization of some receptor subtypes after severe MDMA abuse induced acute 5-HT depletion, and then when the 5-HT rebounds it could cause abberrant neuroplastic changes..

As always, thanks for the insight.

Edit: interesting that 5-HT2A receptors modulate antipsychotic induced dopamine receptor supersensitivity, maybe Pimavanserin is helping with some Parkinson's symptoms that are dopaminergic supersensitivity related as well? https://www.ncbi.nlm.nih.gov/m/pubmed/26508706/

Supersenstivity and constitutive activity are independent -- it just so happens that in this case we are talking about a receptor with constitutive activity.

The supersensitivity only occurs after severe depletion -- ie, not after MDMA.

 

[Limpet_Chicken]

pramipexole is pretty sedating, and too much will result in a pukefest, but the sedation is lurvely, and my god does it ever make one horny as a motherfucker.

 

[Cotcha Yankinov]

The supersensitivity only occurs after severe depletion -- ie, not after MDMA.

I guess I'm curious if it can still happen a bit with severe enough chronic MDMA abuse with someone vulnerable to tryptophan depletion related adverse effects (short form 5-HTTLPR and pre-natal B2 agonist exposure for example, and I suppose that doesn't exclude tryptophan metabolism issues with IDO or having MDD-like pathology).

For example the theory that compounds (possibly including dopamine) are getting inside the serotonin nerve terminal requires low synaptic serotonin levels - inhibition of tryptophan hydroxylase and VMAT and also clearance of 5-HT by metabolism could surely result some level of "5-HT depletion" for some period of time after a severe enough abuse regimen under whatever strenuous circumstances (no sleep, no protein intake, once again vulnerable biology see for example http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1986775/ - "Developmental Exposure to Terbutaline Elicits Presynaptic Serotonergic Hyperactivity in Juvenile and Adolescent Rats" and also just as an aside, interestingly the B2 receptors can be vulnerable to "supersensitivity" from an agonist during developmental stages because some of the compensatory mechanisms may not have developed yet https://www.ncbi.nlm.nih.gov/m/pubmed/8848348/

Sorry to detail thread, there is a pre-natal B2 agonist adverse effects thread with more studies on the B2 sensitivity here http://bluelight.org/vb/threads/800...increase-the-risk-of-negative-effects-of-MDMA

But I guess what I'm saying is there seems to be a link between MDMA's ability to induce neurotoxicity and low 5-HT concentrations - is this just not remotely of the same order in which is necessary to induce supersensitivity? Although one might consider the scenario of distal axotomy and such.

Long abstinent (I believe 3 years average) female MDMA abusers were shown to have up regulated 5-HT2A in cortex, and this was taken as some evidence of neurotoxicity by those authors as I recall https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3538835/ Averaging towards 20% increased expression of 5-HT2A apparently.

I'm curious what percent you would consider supersensitivity? I haven't been able to find too much on that matter. I understand with parkinsons it, because of cell loss, might be tricky to say, even if there is overall loss of 5-HT2A there could be really dense 5-HT2A on some few neurons I suppose.

 

[iksaxophone]

Hahaha, OP, your analogy isn't exactly a scientific model, but I think it is incredibly useful from a harm reduction point of view. I like it as a way of explaining the risks to new users.

 

[Seppi]

studies show amp to be neurotoxic but coke/MPH to be neuroprotective.

Bullshit.

 

[serotonin2A]

I guess I'm curious if it can still happen a bit with severe enough chronic MDMA abuse with someone vulnerable to tryptophan depletion related adverse effects (short form 5-HTTLPR and pre-natal B2 agonist exposure for example, and I suppose that doesn't exclude tryptophan metabolism issues with IDO or having MDD-like pathology).

For example the theory that compounds (possibly including dopamine) are getting inside the serotonin nerve terminal requires low synaptic serotonin levels - inhibition of tryptophan hydroxylase and VMAT and also clearance of 5-HT by metabolism could surely result some level of "5-HT depletion" for some period of time after a severe enough abuse regimen under whatever strenuous circumstances (no sleep, no protein intake, once again vulnerable biology see for example http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1986775/ - "Developmental Exposure to Terbutaline Elicits Presynaptic Serotonergic Hyperactivity in Juvenile and Adolescent Rats" and also just as an aside, interestingly the B2 receptors can be vulnerable to "supersensitivity" from an agonist during developmental stages because some of the compensatory mechanisms may not have developed yet https://www.ncbi.nlm.nih.gov/m/pubmed/8848348/

Sorry to detail thread, there is a pre-natal B2 agonist adverse effects thread with more studies on the B2 sensitivity here http://bluelight.org/vb/threads/800...increase-the-risk-of-negative-effects-of-MDMA

But I guess what I'm saying is there seems to be a link between MDMA's ability to induce neurotoxicity and low 5-HT concentrations - is this just not remotely of the same order in which is necessary to induce supersensitivity? Although one might consider the scenario of distal axotomy and such.

Long abstinent (I believe 3 years average) female MDMA abusers were shown to have up regulated 5-HT2A in cortex, and this was taken as some evidence of neurotoxicity by those authors as I recall https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3538835/ Averaging towards 20% increased expression of 5-HT2A apparently.

I'm curious what percent you would consider supersensitivity? I haven't been able to find too much on that matter. I understand with parkinsons it, because of cell loss, might be tricky to say, even if there is overall loss of 5-HT2A there could be really dense 5-HT2A on some few neurons I suppose.

Supersensitivity is usually defined functionally, not on the basis of receptor number. In addition to changes in receptor expression, it could reflect downstream changes, eg, altered G protein coupling.