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ADHD drugs and dopamine nerve ending damage


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#1 medicineman

  • Location:Kuwait

Posted 10 October 2010 - 03:31 PM


http://www.ncbi.nlm....2?dopt=Abstract


Too bad I cant access the exact substance and doses used. Id be interested in any ideas. A few friends take ritalin and adderrall. Ive always harbored mistrust towards adderall but I was under the impression ritalin had no neurotoxic characteristics. Any ideas?

Ricaurte is one of the researchers. I understand he is a fed merc when it comes to drugs, but Id still like a bit of info.

Edited by medicineman, 10 October 2010 - 03:33 PM.


#2 medievil Re: ADHD drugs and dopamine nerve ending damage

  • Location:Belguim

Posted 10 October 2010 - 03:37 PM

That study noted a drastic dopaminergic loss of 40% after a couple weeks of dosing with obviously doesnt occur in humans (the 2 year study's on amp alone confirm that).

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#3 medievil Re: ADHD drugs and dopamine nerve ending damage

  • Location:Belguim

Posted 10 October 2010 - 03:45 PM

Although evidence for neurotoxicity in rodents derives from studies utilizing very high amphetamine doses, and repeated exposure to lower doses equivalent to the human therapeutic range do not produce toxicity in rodents (e.g., 50), a similar study of non-human primates produced very different results. Adult baboons and squirrel monkeys were treated with a 3:1 mixture of d/l –amphetamine similar to the pharmaceutical Adderal for 4 weeks 53. Plasma concentrations of amphetamine (136 +/− 21 ng/ml) matched the levels reported in human ADHD patients after amphetamine treatment lasting 3 weeks (120 to 140 ng/ml) 54 or 6 weeks in the highest dose (30 mg/day) condition (120 ng/ml) 15. When the animals were sacrificed 2-weeks after the 4 week amphetamine treatment period, both nonhuman primate species showed a 30−50% reduction in striatal dopamine, its major metabolite 3,4-Dihydroxy-Phenylacetic Acid (DOPAC), its rate-limiting enzyme (tyrosine hydroxylase), its membrane transporter, and its vesicular transporter. These consequences are similar, if not identical to the effects of neurotoxic doses in rodents.

...

#4 NR2(x) Re: ADHD drugs and dopamine nerve ending damage

  • Location:USA

Posted 11 October 2010 - 03:58 AM

I thought this was well known, meth addicts have far severer losses, which ultimately lead to parkinsons disease. This effect represents both down regulation and oxidative stress specifically in dopamine neurons. The good news is that Dopamine neurons in the Stratium do replenish, over a 24month window. There are methods avialable to enhance the regeneration process, the major antiaddictive substance being one.

#5 chrono Re: ADHD drugs and dopamine nerve ending damage

  • Location:New England

Posted 11 October 2010 - 05:25 AM

Interesting paper, I hadn't seen this one before. Given AMP's confirmed toxicity at higher dosages, I've always felt that some kind of neurotoxicity at therapeutic dosages was possible. But I agree with medievil, that these results seem pretty implausible. Losing essentially half of dopaminergic function in four weeks? If this model was extended, the people I know who have been on high doses of adderall for literally decades should have Parkinson's...severely.

All in all, this is a pretty cursory study (3 baboons). As the results contradict those from rat and human neuroimaging paradigms, and the implications would be significant for the huge number of people on this drug, it's strange that the author hasn't followed up with a longer-term or more in-depth study in the five years since.

Would still be interested in others' interpretation of this, especially regarding whether there's any way a human could lose half (or more, long-term) of parts of their dopamine system and feel like the treatment is ameliorating dopaminergic deficits.

Update on amphetamine neurotoxicity and its relevance to the treatment of ADHD.
Advokat C.
Louisiana State University

OBJECTIVE: A review of amphetamine treatment for attention-deficit/hyperactivity disorder (ADHD) was conducted, to obtain information on the long-term neurological consequences of this therapy.

METHOD: Several databases were accessed for research articles on the effects of amphetamine in the brain of laboratory animals and ADHD diagnosed individuals.

RESULTS: In early studies, high doses of amphetamine, comparable to amounts used by addicts, were shown to damage dopaminergic pathways. More recent studies, using therapeutic regimens, appear contradictory. One paradigm shows significant decreases in striatal dopamine and transporter density after oral administration of "therapeutic" doses in primates. Another shows morphological evidence of "trophic" dendritic growth in the brains of adult and juvenile rats given systemic injections mimicking "therapeutic" treatment. Imaging studies of ADHD-diagnosed individuals show an increase in striatal dopamine transporter availability that may be reduced by methylphenidate treatment.

CONCLUSION: Clarification of the neurological consequences of chronic AMPH treatment for ADHD is needed.

PMID: 17606768 [PubMed - indexed for MEDLINE]


Edited by chrono, 11 October 2010 - 05:29 AM.


#6 medievil Re: ADHD drugs and dopamine nerve ending damage

  • Location:Belguim

Posted 11 October 2010 - 04:49 PM

There have been a few good discussions about this on mind and muscle, i'l copy a few posts:

Meh, the neurotoxicity of amphetamine in animal studies has little to do with humans. Chiefly, the reserach boils down to three animal models of amphetamine neurotoxicity:

1. Hyperthermia

Amphetamine has a biphasic effect on body temperature; at any dose you'll ever be prescribed by a doctor, it will lower body temp. Only the higher-end dosages will increase temperature. Due to the way the rat metabolism works, these effects are more exaggerated in rat studies as well. I mean, 75mg/kg rat study showing seizures, hyperthermia, and death? That just has little applicability here.

Keep in mind other substitute phenethylamines, like MDMA, can induce hyperthermia with a lower dose than amphetamine. So while this might be relevant for humans in some cases, for someone with ADD taking a Rx'd amount, it's not. If you see the word "hyperthermia" in a study, it's probably irrelevant, because the only effect you're going to get is hypothermia.

2. Excessive Locomotor Activity

Oh, if only this were true of a therapeutic dose in humans, I'd be running ****ing marathons. Another effect that requires a very high dose.

3. Oxidative Stress from Dopamine

Yes, in sufficient quantities, dopamine alone causes tremendous oxidative stress in the brain. One study estimated the dose in humans needed to accomplish this was approximately 4 grams of dextromethamphetamine, which is ~= 6g of d-amp. Again, not an amount a doctor would prescribe.

4. The Primate Study

A recent primate study found neurotoxicity in a primate model with a reasonable (therapeutic) dose of amphetamine. I emailled one of the authors to inquire and he though the mechanism was direct toxicity of amphetamine or ones of its metabolites, similar to some of the data shown with l-dopa. However, this was not shown in that study or any other, and despite the thousands of studies on amphetamine the only neurotoxic mechanisms remain what I identified above.

Part of the problem here is tremendous species differences in the trace amine system; the trace amine receptors are very poorly researched and a new discovery, and are one of the things amphetamine principally binds to. But their expression and effects, and even what trace amine receptors you have (TAAR1, TAAR2, etc) differ significantly, from man, to ape, to rat.

Other issues might be inter-species differences in MAO, CYP2D6, etc.

5. Human Data

The problem is the only human data shows at best about two years with people taking a regular, Rx'd dose. In that time frame and dosing, there is no neurotoxicity or anything. (which seems to contradict the primate study alone) However, longer-term studies have only been done in drug addicts which take high doses and have polydrug abuse, and do not differentiate pre- and post-drug brain states but rather control vs. drug addict brain states, which is poor research when you consider that a dysfunctional dopamine system predisposes one to use stimulants in the first place, so showing that stimulant users have a dysfunctional dopamine system isn't exactly proof of causality on the part of the drug.

The only longer-term data for stimulants includes likelyhood of drug abuse after receiving Rx'd stimulants, which studies show is lower than if the ADD had not been treated. The fact these groups, even 20 years later, were still not abusing drugs, and still seeing a doctor and taking Rx'd medication implies their brains haven't been totally destroyed.

The only thing we have for long-term use of Rx'd amphetamines is anecdotal. I've actually seen some anecdotes of people in this situation, and they didn't require a continually-escalating dosage, and were just fine cognitively. True, the plural of anecdote isn't data, but at least in some cases people aren't hopelessly destroyed by medication here.

6. Supplement vs. Drug vs. Abuse

Seriously, where does this come from? Amphetamine is used to treat certain mental disorders and is a schedule II drug. It is not a supplement, it is not a cognitive enhancement product. Taking a drug prescribed by a doctor for a diagnosed condition is not "drug abuse" under any definition of the term. If you don't have a mental disorder and haven't been prescribed it as part of care by a doctor, don't take amphetamine...

7. Practical Advice

To reuse an old quote, "All things are poison, nothing is without poison. Only the dose determines if something is poisonous or not." The long-term effects of amphetamine in humans remain unclear, but if you are concerned about them, minimize or eliminate your dosage. I can't guarantee this will make your life better off, or make you healthier. In fact, if you truly have strong ADD symptoms that negatively effect your life, you may be engage in behaviors are far more harmful to your health and well-being, and ingest substances that do far greater harm. But hey.

Other options include methylphenidate, which is less toxic in high-dose animal studies, and biofeedback to entrain beta or gamma wave activity. Exercise, good sleeping habits, healthy eating, and good social connectedness should all provide effects that should lessen the amount of stimulants you need to take in the first place. You may not be able to eliminate or "cure" ADD with these things, but you should be able to reduce the symptoms significantly, which will in turn require a lower dose of medication.

Sure, you can take antioxidant supplements and whatnot, and maybe they'll be helpful in general, but we simply don't have data on the long-term use of low-dose amphetamine in humans to begin with, so we certainly don't have any data that shows which supplements are a factor in it.

http://www.mindandmu...6&hl=neurotoxic

And we also have another worrysome study:

Neurotoxicology. 2006 Dec;27(6):1003-6. Epub 2006 Mar 28.
Amphetamine exposure is elevated in Parkinson's disease.

Garwood ER, Bekele W, McCulloch CE, Christine CW.

Pennsylvania State University School of Medicine, USA.
Abstract

BACKGROUND: Since the 1930's, amphetamine drugs have been used therapeutically and recreationally. High doses are associated with acute injury to axon terminals of dopaminergic neurons. It is unknown whether low dose exposure to amphetamine over a prolonged time period is associated with the development of Parkinson's disease (PD).

METHODS: A telephone survey of drug and chemical exposure was administered to patients from three faculty practice clinics at UCSF. Patients were asked to participate if they had been diagnosed with peripheral neuropathy (PN), amyotrophic lateral sclerosis (ALS), or PD between the ages of 40 and 64. Spouses or caregivers were also asked to participate. "Amphetamine exposure" was defined as a prior use of amphetamine, methamphetamine or dextroamphetamine. "Prolonged exposure" was defined as amphetamine use that occurred more than twice a week for > or =3 months or weekly usage for > or =1 year and had to occur before diagnosis of the neurological condition.

RESULTS: Prolonged exposure to either prescribed or non-prescribed amphetamine was common, occurring in 15% with PN (11/76), 13% with ALS (9/72), and 11% with PD (17/158). Prolonged amphetamine exposure was more frequent in diseased patients compared to spouses when all diseases were combined (adjusted OR=3.15, 95% CI 1.42-7.00, p=0.005). When tested alone, only the Parkinson's disease group retained statistical significance (adjusted OR=8.04, 95% CI 1.56-41.4, p=0.013). For most individuals, exposure occurred long before diagnosis (averages: PN 25 years, ALS 28 years, and PD 27 years).

CONCLUSIONS: The elevated rate of prolonged amphetamine exposure in PD is intriguing and bears further investigation.

PMID: 16620991

And read ex-dubio's responses:
http://www.mindandmu...ndpost&p=618985
http://www.mindandmu...ndpost&p=618986
http://www.mindandmu...ndpost&p=618989
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#7 medievil Re: ADHD drugs and dopamine nerve ending damage

  • Location:Belguim

Posted 11 October 2010 - 04:51 PM

ALso lets not forget ricaurte also published a study showing MDMA can give you parkinson after one use, that it causes holes in your brain and another one showing drastic serotogenic loss in humans that take XTC (a further study only saw a 5% serotogenic loss in mdma abusers).

Another study showing dramatic damage fits in that pattern, i wouldnt take that study serieusly.

The other study is differend and should be further investigated, but it appears to be pretty flawed and not very conclusive.

I would also expect some damage, but nothing more then some mild congitive decline wich wont be noticed by the individual.

Edited by medievil, 11 October 2010 - 04:54 PM.


#8 Animal Re: ADHD drugs and dopamine nerve ending damage

  • Location:UK

Posted 11 October 2010 - 05:11 PM

I would also expect some damage, but nothing more then some mild congitive decline wich wont be noticed by the individual.


It will be noticed in later life, the typical ADD child with an amphetamine addiction will have some major deficits by the time they reach 50. Of course they won't recognise this since it will have developed gradually, and they won't have any basis for comparison if they had never taken amphetamine.

#9 medievil Re: ADHD drugs and dopamine nerve ending damage

  • Location:Belguim

Posted 11 October 2010 - 05:18 PM



I would also expect some damage, but nothing more then some mild congitive decline wich wont be noticed by the individual.


the typical ADD child with an amphetamine addiction will have some major deficits by the time they reach 50.

Or maye not, how can you tell with certainity when we dont have any available data?

#10 VoidPointer Re: ADHD drugs and dopamine nerve ending damage

Posted 11 October 2010 - 07:37 PM




I would also expect some damage, but nothing more then some mild congitive decline wich wont be noticed by the individual.


the typical ADD child with an amphetamine addiction will have some major deficits by the time they reach 50.

Or maye not, how can you tell with certainity when we dont have any available data?



Hopefully the OP understands the difference between MPH and AMP.

http://www.ncbi.nlm....les/PMC2701286/


But in all fairness Dexedrine has been around for almost a century, and they do have a general idea of some of the long term effects. To say that all people who take prescribed amounts of AMP get Parkinson s disease is a big stretch with no medical data to back that up.

Adderall is more potent than Dexedrine, and probably more abused. While I have had ADHD since childhood, I have only taken MPH/DexMPH.

No substances are side-effect free, and there is more long term data on Dexedrine than Modafinil, Strattera or Wellbutrin.

#11 bobman Re: ADHD drugs and dopamine nerve ending damage

Posted 11 October 2010 - 08:14 PM



I would also expect some damage, but nothing more then some mild congitive decline wich wont be noticed by the individual.


It will be noticed in later life, the typical ADD child with an amphetamine addiction will have some major deficits by the time they reach 50. Of course they won't recognise this since it will have developed gradually, and they won't have any basis for comparison if they had never taken amphetamine.


Then again some swear by its effects, take for instance Paul Erdos: http://en.wikipedia....wiki/Paul_Erdős

#12 VoidPointer Re: ADHD drugs and dopamine nerve ending damage

Posted 11 October 2010 - 09:36 PM

I have a new hero..

But, given his bio, he was genetically gifted in math from the beginning. Maybe AMP helped him get more work done, but he would have been prolific anyway.

#13 aLurker Re: ADHD drugs and dopamine nerve ending damage

  • Location:Scandinavia

Posted 11 October 2010 - 09:46 PM

Ah, Paul Erdős, the patron saint of amphetamine.

#14 Animal Re: ADHD drugs and dopamine nerve ending damage

  • Location:UK

Posted 11 October 2010 - 10:13 PM




I would also expect some damage, but nothing more then some mild congitive decline wich wont be noticed by the individual.


It will be noticed in later life, the typical ADD child with an amphetamine addiction will have some major deficits by the time they reach 50. Of course they won't recognise this since it will have developed gradually, and they won't have any basis for comparison if they had never taken amphetamine.


Then again some swear by its effects, take for instance Paul Erdos: http://en.wikipedia....wiki/Paul_Erdős


Except he didn't start his daily amphetamine habit until he was almost 60, which is a completely different circumstance to a child addicted from their early teens. The implication is also that after a certain period of abuse he had no creativity or motivation while not under the influence of the drug, since he claims he was unable to produce any mathematical work of worth while on his month long abstinence. This was not the case when he was younger.

#15 bobman Re: ADHD drugs and dopamine nerve ending damage

Posted 11 October 2010 - 10:46 PM





I would also expect some damage, but nothing more then some mild congitive decline wich wont be noticed by the individual.


It will be noticed in later life, the typical ADD child with an amphetamine addiction will have some major deficits by the time they reach 50. Of course they won't recognise this since it will have developed gradually, and they won't have any basis for comparison if they had never taken amphetamine.


Then again some swear by its effects, take for instance Paul Erdos: http://en.wikipedia....wiki/Paul_Erdős


Except he didn't start his daily amphetamine habit until he was almost 60, which is a completely different circumstance to a child addicted from their early teens. The implication is also that after a certain period of abuse he had no creativity or motivation while not under the influence of the drug, since he claims he was unable to produce any mathematical work of worth while on his month long abstinence. This was not the case when he was younger.


That's one potential implication. The other is that the amp was so beneficial that his normal output paled in comparison. Also, I don't see how amphetamine use in your 50's is "completely" different than its use in your teens, at least I don't see how that claim can be made without some empirical corroborative evidence (also you can't have it both ways; either he was benefiting from it, and teens don't, therefore there is a major difference, or he was still degrading his mind, in which case the use has the same relative effect). Furthermore it he was undoubtedly using other stimulants earlier in his life, caffeine is explicitly mentioned. It seems possible that he needed stimulants to be productive, certainly would not be the first case.

#16 NR2(x) Re: ADHD drugs and dopamine nerve ending damage

  • Location:USA

Posted 12 October 2010 - 05:14 AM

Amp does do extensive damage to dopamine neurons, down regulation is the dominant cause. However sufficient dopamine neurons exist to be functional after acute withdrawl. A significant population remain. If you take the drug cronically this isnt the hugest problem.

Amp also does cause significant neurogensis and can improves the structures and communicative efficiency of things like the NAC. I will go look for some summaries,science. There are elements of behavoural sentistization, which can improve productivity dramactically. Complicated issues

The real problem with AMP is that the risk of strokes and heart failures raises rapidly, you'd be lucky to reach sixty. Then again I have heard stimulants described by a doc as the safest of medicines, obvious context required.

#17 aLurker Re: ADHD drugs and dopamine nerve ending damage

  • Location:Scandinavia

Posted 12 October 2010 - 07:21 AM

Amp does do extensive damage to dopamine neurons, down regulation is the dominant cause. However sufficient dopamine neurons exist to be functional after acute withdrawl. A significant population remain. If you take the drug cronically this isnt the hugest problem.

Amp also does cause significant neurogensis and can improves the structures and communicative efficiency of things like the NAC. I will go look for some summaries,science. There are elements of behavoural sentistization, which can improve productivity dramactically. Complicated issues

The real problem with AMP is that the risk of strokes and heart failures raises rapidly, you'd be lucky to reach sixty. Then again I have heard stimulants described by a doc as the safest of medicines, obvious context required.


It would be nice if you also provided some sources that therapeutic use causes heart damage. Here is some news article about a study for instance but that one is about abuse and not about the doses relevant for ADHD. There is a big difference between use and abuse.

Edited by aLurker, 12 October 2010 - 07:57 AM.


#18 NR2(x) Re: ADHD drugs and dopamine nerve ending damage

  • Location:USA

Posted 12 October 2010 - 11:24 AM

Its hard to get info on the safety of medicine still on the market.....
The FDA has directed manufactures to declare a black box warning regarding cardiovascular risks of stimulants

http://www.fda.gov/N...7/ucm108849.htm

#19 medievil Re: ADHD drugs and dopamine nerve ending damage

  • Location:Belguim

Posted 12 October 2010 - 12:15 PM

Amp does do extensive damage to dopamine neurons, down regulation is the dominant cause. However sufficient dopamine neurons exist to be functional after acute withdrawl. A significant population remain. If you take the drug cronically this isnt the hugest problem.

Amp also does cause significant neurogensis and can improves the structures and communicative efficiency of things like the NAC. I will go look for some summaries,science. There are elements of behavoural sentistization, which can improve productivity dramactically. Complicated issues

The real problem with AMP is that the risk of strokes and heart failures raises rapidly, you'd be lucky to reach sixty. Then again I have heard stimulants described by a doc as the safest of medicines, obvious context required.

Downregulation is not "extensive damage".

#20 medievil Re: ADHD drugs and dopamine nerve ending damage

  • Location:Belguim

Posted 12 October 2010 - 12:21 PM

The real problem with AMP is that the risk of strokes and heart failures raises rapidly, you'd be lucky to reach sixty.

Reading ricaurte's magazine?

#21 NR2(x) Re: ADHD drugs and dopamine nerve ending damage

  • Location:USA

Posted 13 October 2010 - 04:15 AM

The body achieves down regulation in many ways, loss of a significant fraction of said neurons is obviously damage to those said neurons.
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#22 medievil Re: ADHD drugs and dopamine nerve ending damage

  • Location:Belguim

Posted 13 October 2010 - 10:16 AM

The body achieves down regulation in many ways, loss of a significant fraction of said neurons is obviously damage to those said neurons.

But they also upregulate again, the body down and upregulates at a constant time, this has nothing to do with damage.

#23 Ark Re: ADHD drugs and dopamine nerve ending damage

  • Location:Kent Washington

Posted 13 October 2010 - 10:26 AM

I think NR2(x) is referring to axon clipping which causes serious neurological problems.

Edited by Ark, 13 October 2010 - 10:27 AM.


#24 medievil Re: ADHD drugs and dopamine nerve ending damage

  • Location:Belguim

Posted 13 October 2010 - 12:48 PM

I think NR2(x) is referring to axon clipping which causes serious neurological problems.

Okay, i'm not really sure about the exact mechanisms at play in amp neurotoxiticy.

However monoamine depletion is used as a measure for toxiticy, if this occurs in humans we would see a dramatic loss of effiacy in ADHD patients over time, wich usually doesnt occur because the D4 receptors dont downregulate.

Also i would "axon clipping" or any other damage expect to cause serieus neurological problems like you say but there arent any documented in the literature.

For example we know that antipsychotics cause tardive dyskinesia in 4% of all patients with long term use, and selling antipsychotics is big business so the argument that that would prevent long term side effects from being documented is nonsense.

Yet with amphetamine's we dont have any of those problems documented why? Is amphetamine supposed to be special were all long term side effects go unnoticed or something?

#25 Ark Re: ADHD drugs and dopamine nerve ending damage

  • Location:Kent Washington

Posted 13 October 2010 - 01:05 PM


I think NR2(x) is referring to axon clipping which causes serious neurological problems.

Okay, i'm not really sure about the exact mechanisms at play in amp neurotoxiticy.

However monoamine depletion is used as a measure for toxiticy, if this occurs in humans we would see a dramatic loss of effiacy in ADHD patients over time, wich usually doesnt occur because the D4 receptors dont downregulate.

Also i would "axon clipping" or any other damage expect to cause serieus neurological problems like you say but there arent any documented in the literature.

For example we know that antipsychotics cause tardive dyskinesia in 4% of all patients with long term use, and selling antipsychotics is big business so the argument that that would prevent long term side effects from being documented is nonsense.

Yet with amphetamine's we dont have any of those problems documented why? Is amphetamine supposed to be special were all long term side effects go unnoticed or something?


If you have a moment please review this: Dopaminergic neuronal degeneration and motor impairments following axon terminal lesion by intrastriatal 6-hydroxydopamine in the rat

C. S. Lee**, H. Sauer*, † and A. Björklund
* Department of Medical Cell Research, University of Lund, Biskopsgatan 5, S-223 62, Lund, Sweden
** Neurodegenerative Disorders Centre, Vancouver Hospital and Health Sciences Centre, Purdy Pavilion, 2221 Wesbrook Mall, Vancouver, BC, Canada
Accepted 29 November 1995. ; Available online 2 March 1999.
Abstract
6-Hydroxydopamine-induced nerve terminal lesion of the nigrostriatal system may provide a partial lesion model of Parkinson's disease useful for the assessment of neuroprotective treatments and behavioral recovery after therapeutic intervention. The aim of the present study was to assess the retrograde degenerative changes in the dopaminergic neurons of the substantia nigra and the associated behavioral and neurochemical consequences of intrastriatal injections of 6-hydroxydopamine in young adult rats. Four groups of rats were stereotaxically injected in the right striatum with graded doses of 6-hydroxydopamine ranging from 0 to 20 μg. Structural and functional deficits were quantified by tyrosine hydroxylase-immunoreactive nigral cell numbers, striatal dopamine content, skilled paw use, and drug-induced rotation. The results show that striatal 6-hydroxydopamine lesions produce dose-dependent decreases in striatal dopamine levels and tyrosine hydroxylase-immunoreactive cell numbers in the ipsilateral substantia nigra, accompanied by a significant long-lasting atrophy of the remaining dopaminergic neurons. Paw reaching test scores on the side contralateral to the lesion were non-linearly correlated with dopaminergic neuronal cell loss and exhibited a clear symptomatic threshold such that impaired paw use appeared only after > 50% loss of nigral dopamine neurons or a reduction of 60–80% of striatal dopamine levels. The behavioral, cellular, and neurochemical effects of the nerve terminal lesion thus bear some resemblance to the early stages of Parkinson's disease, where the severity of motor impairment is correlated with the loss of dopamine in the striatum and dopaminergic neuronal loss in the substantia nigra.
Rats with intrastriatal 6-hydroxydopamine lesions thus provide a model of progressive dopamine neuron degeneration useful not only for the exploration of neuroprotective therapeutic intervention but also for the study of mechanisms of functional and structural recovery after subtotal damage of the nigrostriatal dopamine system.
Author Keywords: substantia nigra; striatum; 6-hydroxydopamine; paw-reaching; degeneration; Parkinson's disease

Abbreviations: ANOVA, analysis of variance; DA, dopamine; DOPAC, 3,4-dihydroxyphenyl acetic acid; -IR, -immunoreactive; MTN, medial terminal nucleus of the accessory optic tract; NSS, normal swine serum; 6OHDA, 6-hydroxydopamine; PB, phosphate buffer; PD, Parkinson's disease; TH, tyrosine hydroxylase; VM, ventral mesencephalon

#26 medievil Re: ADHD drugs and dopamine nerve ending damage

  • Location:Belguim

Posted 13 October 2010 - 01:07 PM

Yes but hyperthermia is essential for neurotoxic damage in the rats and therapeutic doses in humans dont produce any hyperthermia.

#27 Ark Re: ADHD drugs and dopamine nerve ending damage

  • Location:Kent Washington

Posted 13 October 2010 - 01:08 PM

Yes but hyperthermia is essential for neurotoxic damage in the rats and therapeutic doses in humans dont produce any hyperthermia.

source?

#28 medievil Re: ADHD drugs and dopamine nerve ending damage

  • Location:Belguim

Posted 13 October 2010 - 01:11 PM

But this is about meth, will need to do some digging on amphetamine itself:

Further studies of the role of hyperthermia in methamphetamine neurotoxicity.
J F Bowyer, D L Davies, L Schmued, H W Broening, G D Newport, W Slikker, Jr and R R Holson
+ Author Affiliations

Division of Neurotoxicology, National Center for Toxicological Research, Jefferson, Arkansas.
Abstract

The depletion of striatal dopamine (DA) that can occur after methamphetamine (METH) administration has been linked to METH-induced hyperthermia. The relationship between METH-induced hyperthermia, neurotoxicity (striatal DA depletions) and compounds that protect against METH neurotoxicity was further investigated in this study. Typically, rats exposed to METH die when their body temperatures exceed 41.3 degrees C but such hyperthermic rats can be saved by hypothermic intervention. Subsequently, rats saved by hypothermic intervention have greater depletion of striatal DA at an earlier time of onset (18 hr or less post-METH) than do METH-exposed rats that do not attain such high temperatures. Striatal damage was present 3 days post-METH in these hyperthermic rats, as assessed by silver degeneration of terminals and increases in the astrocytes that express glial fibrillary acidic protein immunoreactivity. By contrast, alterations in the number of [3H]dizoclipine (MK-801) binding sites in cortical or striatal membranes at 1, 3 or 14 days post-METH were not detected. The experiments showed that mean and maximal body temperature correlated well with striatal DA concentrations 3 days post-METH (r = -0.77, n = 5, which suggests a role for hyperthermia in METH neurotoxicity. However, hyperthermia (alone or with haloperidol present) induced by high ambient temperatures did not deplete striatal DA in the absence of METH. Haloperidol, diazepam and MK-801 all reduced METH-induced striatal DA depletion to a degree predicted by their inhibition of hyperthermia and increased ambient temperature abolished their neuroprotection. Although an interleukin-1 receptor antagonist reduced maximal body temperature enough to lower the lethality rate, it did not reduce the temperature sufficiently to block METH neurotoxicity. It was concluded that short- and long-term decreases in striatal DA levels depend on the degree of hyperthermia produced during METH exposure but cannot be produced by hyperthermia alone. In addition, several agents that block DA depletions do so by inhibiting METH-induced hyperthermia. Finally, the results suggested a role for interleukin-1 in the extreme hyperthermia and lethality produced by METH.



#29 chrono Re: ADHD drugs and dopamine nerve ending damage

  • Location:New England

Posted 13 October 2010 - 06:28 PM

This conversation suddenly got pretty confused.

Amp does do extensive damage to dopamine neurons, down regulation is the dominant cause.

The body achieves down regulation in many ways, loss of a significant fraction of said neurons is obviously damage to those said neurons.

You're using this term incorrectly; downregulation usually refers to a decrease in the number of receptors, or release of the neurotransmitter, in response to increased levels. I'd like to see some evidence that the brain "downregulates" by killing off significant parts of its own neurological systems, because it would have implications for literally everything we discuss here.


If you have a moment please review this: Dopaminergic neuronal degeneration and motor impairments following axon terminal lesion by intrastriatal 6-hydroxydopamine in the rat

Can you clarify what relation this paper has to AMP toxicity? Lesioning dopamine axons/neurons will result in a loss of function and DA release, but Oxidopamine is a neurotoxin, and I don't see what this tells us without demonstrating that AMP produces this lesioning at the dosages we're talking about.

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#30 Animal Re: ADHD drugs and dopamine nerve ending damage

  • Location:UK

Posted 13 October 2010 - 10:08 PM

There is so much evidence for the detrimental effects of amphetamine administration over an extended time period I don't know why anyone is trying to argue the opposite; unless of course it's just to reassure themselves about their amphetamine habits.

Chronic amphetamine treatment reduces NGF and BDNF in the rat brain

Francesco Angelucciab, Susanne H.M. Grubera, Aram El Khourya, Pietro Attilio Tonalib, Aleksander A. MathéaCorresponding Author Informationemail address

Received 3 January 2007; received in revised form 19 February 2007; accepted 6 March 2007.
Abstract

Amphetamines (methamphetamine and d-amphetamine) are dopaminergic and noradrenergic agonists and are highly addictive drugs with neurotoxic effect on the brain. In human subjects, it has also been observed that amphetamine causes psychosis resembling positive symptoms of schizophrenia. Neurotrophins are molecules involved in neuronal survival and plasticity and protect neurons against (BDNF) are the most abundant neurotrophins in the central nervous system (CNS) and are important survival factors for cholinergic and dopaminergic neurons. Interestingly, it has been proposed that deficits in the production or utilization of neurotrophins participate in the pathogenesis of schizophrenia. In this study in order to investigate the mechanism of amphetamine-induced neurotoxicity and further elucidate the role of neurotrophins in the pathogenesis of schizophrenia we administered intraperitoneally d-amphetamine for 8 days to rats and measured the levels of neurotrophins NGF and BDNF in selected brain regions by ELISA. Amphetamine reduced NGF levels in the hippocampus, occipital cortex and hypothalamus and of BDNF in the occipital cortex and hypothalamus. Thus the present data indicate that chronic amphetamine can reduce the levels of NGF and BDNF in selected brain regions. This reduction may account for some of the effects of amphetamine in the CNS neurons and provides evidences for the role of neurotrophins in schizophrenia.


I wouldn't even need to see studies to confirm it's negative effects, it's observed all the time anecdotally in chronic users as their cognition deteriorates. It's the same as the MDMA studies which seem to indicate minimal damage. When only specific neurological structures are focused on, it can be difficult to ascertain the actual extent of the detrimental effects on the individual as a whole. But when you speak to the majority of long term chronic users of amphetamines or MDMA they will confirm the gradual decline in cognition/personality/mood that they have experienced. I mean we get enough individuals on this site looking for a solution to their drug induced deficits, whether there is clinical evidence to support it or not.

Medievil, you can't even claim to maintain only therapeutic doses of amphetamines either, probably like the majority of ADD addicts. It's a substance that is often abused by individuals who are prescribed it, simply because of the dopaminergic nature of its effects. So lets not keep using the 'therapeutic doses' excuse to try and pretend that it's a perfectly healthy drug to be hooked on for life.


Also the person who said:

I don't see how amphetamine use in your 50's is "completely" different than its use in your teens


Is obviously a bit ignorant if they can't see the difference between a 60 year old man who becomes an addict and dies 20 years later, suffering from mental decline which can arguably be attributed to his age; and a 12 year old child addict who uses amphetamines daily for 40 years and suffers the cognitive consequences of this in his 50's. Of course the fact that the child's brain is still developing is a major factor also.
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