Frissons and dopaminergic neurotoxicity

[arohydro]

Hello,

I'd like to deepen my understanding of these phenomena, an understanding which I admit is quite superficial and lacking.

I was daydreaming the other day and came upon an interesting question... I was wondering if it were possible that frissons, that chill-like experience one has during a piece of very moving music, art, literature, etc, which I believe have a correlation to a release of dopamine in the striatum (among other places), could worsen neurotoxicity when experienced in those taking adderall or other neurotoxic agents.

If not, why is it that this does not happen? Why is it not as simple as more dopamine being released = further dopaminergic neurotoxicity? What mediates it?

Again, I realize I'm looking at this from a very basic viewpoint without any of the true nitty-gritty details which make valid an assertion like this. That's why I'm coming to you!

Thanks.

 

[sekio]

It seems unlikely to me. I think frissions involve a lot more than an elevation of dopamine, and even then... if it were as simple as "more DA=more toxicity" then drugs like methylphenidate would be notably more neurotoxic.

I think the toxicity of amphetamine comes from larger doses, where transporter reversal leads to a massive increase in neurotransmitter concentrations unlike anything "normally" achievable regardless of whether or not there is a pleasurable stimulus.

 

[Hammilton]

I think if dopamine release was the reason for "frissons" stimulant addicts (while off the drug) and those treated with neuroleptics would be unable to experience them. Anyone wanna test this?

More dopamine is definitely more neurotoxic, though. This is most easily demonstrated with a less complicated drug- L-dopa, a drug that reliably produces neurotoxicity, but which has such incredible curative powers for patients with Parkinson's that it's widely used. Parkinson's patients, however, will wait as long as they can before they start on L-Dopa because once it's started it more or less must be maintained because the changes in the brain it produces don't seem to revert after discontinuation.

 

[sekio]

L-dopa, a drug that reliably produces neurotoxicity

At what sort of levels? Wouldn't that mean fava beans would be neurotoxic then?

 

[arohydro]

Alriiight, I got responses from not one, but TWO contributors I happen to hold in quite high esteem, having read many of your posts over the years. Thanks!

Ok, so yes, methylphenidate suggests that more dopamine =/= more neurotoxicity in all instances, but it has a mechanism by which it mediates neurotoxicity when COMBINED with amphetamine, rather than simply worsening it, and when used alone it does not induce the environment by which neurotoxicity occurs, as far as I'm aware.

However, if the environment were initially staged, such as with adderall use, why is it that a frisson, lacking such a mediative action, or being more basic in its introduction of dopamine, wouldn't then contribute to & exacerbate that environment? Also, if that were the case, wouldn't more and more instances of reward, or whatever natural increases of dopamine exist, be a contributing factor to neurotoxicity during amphetamine use? I mean, again, I really lack the kind of neuropharmacological knowledge base necessary to make these assertions, it just seems like if a frisson is a flood of dopamine, that it would provide a surge of reagent for the oh-so-familiar (yet to this day, elusive) nasty oxidative process.

The only sources I have for an increase in dopamine during the frisson response are ARTICLES that can be found with a quick google search, rather than the proper study it was based upon.

Also, that would be a great way to test this out, if there are any former stimulant users or neuroleptic users that would like to throw in their two cents as to whether or not they lack this capacity, or if it decreased in frequency or severity upon their use, it would be AWESOME.

 

[AlphaMethylPhenyl]

[I'm impolite towards others sometimes]

I've been on both, though never a very high dose of a stimulant. Anti-psychotics shut down all pleasure. As for amphetamine,

Amphetamine does things to your neurons which wouldn't, couldn't be done otherwise. Its not so much the presence of more dopamine, but the way by which this is achieved.

And you'd be hard pressed to find a study which concludes methylphenidate as neurotoxic.

 

[sekio]

AFAICT nobody has shown a correlation between amp users "feeling good" (e.g. "high dopamine levels") and dopaminergic brain damage; that is not to say that amphetamine isn't toxic, but I don't think the damage is correlated to "how much dopamine released during pleasurable events".

it just seems like if a frisson is a flood of dopamine,

The problem is, dopamine is very rarely ever released on its own... it is almost always paired with other N/Ts being released. And as I said before, "native" dopamine release does not ever usually build to hazardous levels. I seem to recall that amphetamines are notably more toxic than e.g. mph because they promote oxidative and thermal stress in the neuron far more than reuptake inhibitors do.

 

[Hammilton]

I've been on both, though never a very high dose of a stimulant. Anti-psychotics shut down all pleasure. As for amphetamine,

Amphetamine does things to your neurons which wouldn't, couldn't be done otherwise. Its not so much the presence of more dopamine, but the way by which this is achieved.

And you'd be hard pressed to find a study which concludes methylphenidate as neurotoxic.

I asked whether neuroleptics would inhibit "frissons" as this would provide a clue as to whether they are produced via a dopaminergic pathway. Anyone wanting to study whether these are produced via a dopaminergic pathway would look to see whether neuroleptics prevent frissons. A broad dopamine receptor antagonist would be needed. Though if that produced positive results, it would make sense to continue studying with selective DA antagonists to determine whether an individual receptor is responsible.

Additionally, neuroleptics have been shown to increase amphetamine and cocaine self administration (but I haven't read the full study to see whether this is only in addicts exposed to these drugs prior to anti-psychotic treatment). Naloxone has been shown to block amphetamine self administration in at least one study, where neuroleptics only attentuated it. That is certainly meaningful.


[Save it for PM]

AFAICT nobody has shown a correlation between amp users "feeling good" (e.g. "high dopamine levels") and dopaminergic brain damage; that is not to say that amphetamine isn't toxic, but I don't think the damage is correlated to "how much dopamine released during pleasurable events".

I'm pretty sure that amphetamine dose level is directly correlated with dopaminergic neurotoxicity. Presumably higher doses also equal higher dopamine levels. This also means higher levels of dopamine metabolites. That's probably meaningful given that MAOI's inhibit neurotoxicity (but increase risk of death, fwiw).

I don't think there's any evidence that natural, non-drug/non-sex related causes of dopamine release are neurotoxic, period. The oxidative stress is directly correlated with dopamine levels (as it's the dopamine being metabolized that causes the stress!). I don't believe that thermal stress can be considered at the neuronal level. Instead whole body temp rises are to blame (at least with regard to serotonergic neurotoxicity, I don't recall it being mentioned in regards to dopaminergic neurotoxicity).

At what sort of levels? Wouldn't that mean fava beans would be neurotoxic then?

That's a good question. They're not administered with a peripheral dopa decarboxylase inhibitor, either, which is probably related. I'd guess that the majority of the L-dopa in Fava beans is being metabolized to dopamine in the peripheral nervous system, and then unable to penetrate the CNS, as with pharmaceutical L-Dopa.

 

[sekio]

Here's a related gedankenexperiment: Is orgasm neurotoxic under amphetamine treatment?

 

[MrSpeedyG]

I don't think frissons themselves cause neurotoxicity... My understanding, I do lack real chemistry knowledge, is that if for whatever reason a natural dopamine release occured/frisson that:

One; the amount of extra dopamine would not be enough to overwhelm the anti-oxidant system

Two; even if it was enough to do so, it is not prolonged and is usually just a quick burst and easily swept up by the antioxidant system

I think, and this is going off what I have gathered so far in my reading and as said I do not have a degree in this field or any real strong knowledge of it, the whole theory of dopamine being the cause for toxicity in amphetamine/dopamine releasing agents is that they cause a prolonged, high level of dopamine which eventually overwhelms the endogenous human anti-oxidant system and thus free radicals then attack the cells etc etc and this combined with all the typical conditions seen with proven neurotoxic substance abuse involves a combo of hyperthermia, dehydration, lack of food in turn glucose for the brain as energy aswell as nutrients meaning antioxidants and the building block for antioxidants... then ATP/cellular/mitochondiral energy degeneration from the faster process/metabolism... As you can see obviously a lot more invovled than "more dopamine=neurotoxicity". Then ofcourse amphetamine or its metabolite being neurotoxic... but we are straying from teh point here.

Frissons whilst on a substance such as meth/MDMA or amphetamine in my experience however seem to be much more pronounced than when sober and I guess it could cause an extra surge ontop of whatever is already being released, but again not prolonged...

There is a study somehwere on MDMA and music both working synergtisically and enhancing each other and maybe that could shed some light on this topic if it meant the frissons caused from the music were enhanced somehow due to the MDMA/or insert whatever monoaminergic substance

 

[Hammilton]

Here's a related gedankenexperiment: Is orgasm neurotoxic under amphetamine treatment?

Hmm... This is a study I could be down with... literally? lol

Man, you'd need two groups, one to masturbate continuously without speed, another to masturbate continuously with speed. For practical purposes, Cialis should probably be consumed by all involved. And lube. I imagine women would have an easier time in a study where they were asked to orgasm as many times as possible over the course of three days.

Imagine taking that one to an IRB!

Really this whole question is somewhat pointless. A natural process that occurs sparingly isn't neurotoxic by definition. This thread would be more interesting if frissons were considered without the introduction of a question of neurotoxicity.


However, thanks to Sekio above, I am now wondering whether there might be "neurotoxicity" associated with extremely heavy masturbation / sex addiction. That's actually an interesting question. Can an addiction to a completely natural but extremely pleasurable activity which is programmed biologically- have negative consequences on brain functioning?! I mean, how is it that the most pleasurable thing you can do without drugs needs a hormones to drive it in addition to the drive to repeat any pleasurable activity the dopaminergic system provides? It would seem that the propensity to sex addiction was designed to be more common than any other non-drug addiction. It's amazing it's not more common than it is, actually.

Now I'm wondering about rates of Parkinson's disease and RLS in Sex Addicts compared to the general population. Maybe no different, but the risk of Parkinson's is 60% higher in those who used amphetamines (http://www.sciencedaily.com/releases/2011/02/110220193013.htm), though how they determined abuse, I dunno. I have some damage caused by manganese poisoning, and my muscles feel more normal after taking a low dose of amphetamine, but the two days after doing so I'm much stiffer than I was previously.

Frissons whilst on a substance such as meth/MDMA or amphetamine in my experience however seem to be much more pronounced than when sober and I guess it could cause an extra surge ontop of whatever is already being released, but again not prolonged...

While I'd agree with the idea that they're more pronounced on these drugs, I'm still not willing to assume that it's caused by dopamine flooding. These drugs have the mind in a place that's ready to be excited and thrilled, and so it would make sense that frissons would be more common. They also tend to make most enjoyable things more enjoyable, it only makes sense that if you're high the frisson would be "higher" then when you're sober.

 

[arohydro]

Thank you all for your responses.

It appears as if some of the points I've brought up have been overshadowed by a personal disagreement that has hopefully now concluded, and to be completely honest I do not appreciate having my thread de-railed, though I am not pointing fingers any which way and am perfectly satisfied to leave it at expressing my slight frustration. Especially considering I received some insightful additions in its midst, by its participants no less.

The general understanding I've siphoned from reading your responses seems to be that my question was about whether or not frissons could be neurotoxic in their own right. It is not.

I am essentially asking if, in the throes of an already precarious battle between the body's antioxidant defense and the radical generation of dopaminergic metabolism, a frisson could (however) briefly overwhelm those defenses, tipping the scales enough so as to exacerbate the severity of whatever toxicity the system might have already been leading up to, or even to push it over the edge if it would not have reached that point on its own. My best stab at compiling an understanding through what you all have collectively stated here is that it takes quite a bit of extra dopamine to reach that neurotoxic threshold, and since endogenous processes simply lack the capacity to nurture the proper environment, consequently their intensity must be of such a lower order of magnitude as to be negligible in the grand scheme of things. Am I correct here?

http://www.nature.com/neuro/journal/v14/n2/full/nn.2726.html

Here's an abstract.

Given that most of your understandings of this type of thing have a great deal more breadth and depth than mine, I am keen to listen and learn from you. However, I love details!

Also, that orgasm deal was precisely the type of question I was trying to lead into with this thread, and I believe I have a sentence above that details it a bit better - if other bouts of typical reward experienced, such as orgasm, could have those side effects, especially during amphetamine treatment.

 

[pofacedhoe]

[removed]


as a diagnosed person with bipolar in remission those waves and rushes to me have more to do with electric feelings than neurotransmitters. i have no research to back up my point but they feel like electricity and lots of anti epilepsy meds are good for calming down mania. i have touched electric fences and batteries so i can tell that rush feels electric. just a hunch...

 

[sekio]

I just had to delete, by my count, thirteen (too many) rude/pointed posts (and remove more sections of posts). Let's all keep this discussion civil and on-topic.

I am essentially asking if, in the throes of an already precarious battle between the body's antioxidant defense and the radical generation of dopaminergic metabolism, a frisson could (however) briefly overwhelm those defenses, tipping the scales enough so as to exacerbate the severity of whatever toxicity the system might have already been leading up to, or even to push it over the edge if it would not have reached that point on its own.

I don't think oxidative damage is a binary choice, where DA reaches some threshold and then damage begins... pretty sure it's all proportional.

Gedankenexperiment number two: Is the use of slot machines neurotoxic (elevation of DA)? How about chronic problem gambling?
Do depressed people on amphetamine retain more nervous function than exuberant, outgoing people?

My gut feeling says, if you are using amphetamine so much that a frission would incur toxicity, what happens if you tripped on a curb, or spilled hot coffee on yourself, or something? Would not the fight-or-flight monoamine release exacerbate neurotox?

I think amphetamine is in a "league of its own" with regards to oxidative stress induction, and no one "native" biological stimulus would be able to tip the scales. A bigger concern, to me, is the maintenance of proper sugar, salt, and water levels ( & core temperature monitoring). Especially with MDMA a lot of the damage is severely exacerbated by heat.

 

[Hammilton]

I believe that there are cases of catecholamine surge resulting in death, not drug related, that is.

 

[TCMVegas]

Since it ties in with the (effective) thread topic, does anyone know of any good papers about brain changes seen in amphetamine users?

Edit: taking it to relevant thread

 

[AlphaMethylPhenyl]

^Do you mean in chronic, high dosing or just regular doses? EA posted a good one

toxicity:
http://jpet.aspetjournals.org/content/315/1/91.long
http://pharmacology.ucsd.edu/graduate/courseinfo/documents/ricaurteadhd.pdf


This one's quite interesting: http://www.wikigenes.org/e/ref/e/7197513.html

http://stroke.ahajournals.org/content/29/11/2381.short

http://www.ncbi.nlm.nih.gov/m/pubmed/12213320/

Just a few I have. If you want papers in regards to specific changes/effects then I could be of more help.