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How reversible is DAT receptor upregulation from long-term ADHD medication use?

dopamine

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#1 InquilineKea

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Posted 03 February 2012 - 01:11 AM


A mechanism for ADHD stimulant medication tolerance has now been found. See http://neurosciencen...ains-adapt-dat/
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#2 hooter

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Posted 03 February 2012 - 06:56 AM

This is good news for me, screw reversing that. I'd rather have more drive than no drive. If people who don't have ADHD take it, they've got a bit of a problem.

Edited by hooter, 03 February 2012 - 06:58 AM.


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#3 sparkk51

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Posted 03 February 2012 - 09:26 PM

So, if it isn't reversible. I wonder what long term dopamine antagonism would do.

#4 jillin

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Posted 05 February 2012 - 02:57 AM

If the brain can adapt to increased concentrations of dopamine caused by stimulants by producing complementary levels of DATs to ameliorate the imbalance, when the dopamine levels drop, I would assume the brain can modulate itself back to the original state. As with anything in the human body, there is a strict predefined equilibrium point set by our genes; in case of chronic medication where there's a slow shift in this equilibrium, the body's compensatory mechanisms will activate to achieve equilibrium again. Of course, if you can achieve equilibrium going in one direction, I am sure the body is capable of doing the vice versa. I also don't perceive an actual issue for people that take these ADHD stimulants when they aren't afflicted with the ailment -- if anything their bodies will adjust to the elevated dopamine concentrations faster -- probably cause them to take higher dosages for a similar effect -- might spur signs of addiction.

#5 InquilineKea

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Posted 05 February 2012 - 08:31 PM

^it's possible that this is not the case though. Have you ever heard of hysteresis? http://en.wikipedia....wiki/Hysteresis

#6 sparkk51

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Posted 06 February 2012 - 01:13 AM

Wouldn't the case of hysteresis be a good thing? I mean, your mind and body is, ultimately, adapting to the effects of higher dopamine levels. Therefore, you should be more accustomed to higher levels rather than lower.

An analogy to this may be, when one stretches out a rubber band, the band will mostly revert back when the stretching force is removed, but it will be stretched out a little more.

#7 jillin

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Posted 06 February 2012 - 05:53 AM

I am aware of hysteresis as there has been many, many examples and cases written about it in science/medical journals -- it's why I mentioned normal people would probably adjust to the alien environment faster than that of an ADHD sufferer [rise in DA levels, body initiates mechanisms to ameliorate deviation from equilibrium; if a hysteresis loop occurs, it is highly possible there will be a mechanism to normalize its effects; it would take longer for ADHD sufferers because their initial DA levels are lowered and will take longer to have the stimulant's modulation effects summate to initialize said mechanisms]. With that said, I don't want to delude myself or anybody reading my posts into thinking I am an expert in this particular realm of physical science -- but I did account for it when I wrote my response. The thing with hysteresis arising in biological systems is that the human body is very smart in how it deals with these fundamental thermodynamic changes that promotes undesirable shifts in the homeostatic equilibrium. Sparkk51's analogy is pretty solid for what I'm trying to explain; sure, with elevated DA levels in the brain due to exogenous means may generate a bio-molecular hysteresis-like system loop to sustain the new environment, but you shouldn't assume the body doesn't have compensatory mechanisms in place to recreate initial conditions. Biological/bio-chemical systems tend to have mechanisms that either prevent or to compensate for such loops to occur: a simple example would be cell apoptosis; a complex example is the proposed role of non-coding DNA in regulation and modification of the human genome. From what I see, the only way for an individual to experience an irreversible change [meaning living chronically with new homeostatic equilibrium] such as this AFTER ceasing the medication that resulted in the new environment, two things need to occur: first, have irreversible agonists of dopaminergic cells or antagonists of DA re-uptakers to initiate the shift in equilibrium; second the new cellular environment needs to be able to generate genomic changes so that either the irreversible agonist/antagonist bound cellular/compound modalities affected are left alone [does not get broken down/go through apoptosis] -- this goes into the realms of cancer, or somehow alter coding sequences for these affected cellular/compound modalities so that they will be able to sustain the new environment after the original affected cellular/compound modalities have been purged from the system. Of course, all of this can happen but it is unlikely.

#8 sparkk51

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Posted 06 February 2012 - 02:28 PM

Jillin, are you thinking about epigenetic change? I am not entirely sure, because I am not confident I fully understand what epigenetics is.

#9 jillin

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Posted 07 February 2012 - 02:40 AM

Epigenetics, to put simply, basing off of what I've learned in introductory to genetics from University 3 years back is: the study of genetics that correlate fundamental hereditary genomic mechanisms with environmentally induced alteration mechanisms to cause deviations from inceptive genome. Of course this is a broad "hand-waving" definition because epigenetics is a beast of a subject, and I am far from being perspicacious regarding this subject -- I am only a neuroscience/neurobiology graduate student. To answer your question, what I wrote about can be related to epigenetics as even breathing in carcinogens in the air has been deemed to be a factor that can produce epigenetic changes; I'm sure chronic medication of stimulants can easily be grouped into a similar category. However, what I meant from my previous post [which I can see now is the opposite of concise, apologies], is basically the bare-bone cellular mechanisms that allow for mutations to arise and persist, i.e. DNA/RNA polymerase erroneous replication of base sequence and/or inability to identify these faults and immediate correct them like they normally do [or basically any malfunctioning of the step(s) of the central dogma].

#10 kassem23

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Posted 07 February 2012 - 05:41 AM

Dr Paolo Fusar-Poli and Professor Katya Rubia at the IoP at King’s led the research. Prof Rubia says: ‘There is currently no evidence for the long-term effectiveness of stimulant medication. In fact, there is evidence that the effect of medication diminishes over time and we know from clinicians that medication doses often need to be increased over time to be as effective as they were initially. Our findings could help explain why stimulants work very well in the short term but not so well long-term.’


1. What evidence? It is near-impossible, and also unethical to employ the kind of randomized studies that would be needed to investigate this (>2 years), you would need to have a control group with diagnosed ADHD given placebo, and another group of ADHD given amphetamine/methylphenidate and in the long-term doing a study like that is just plain wrong. The medications usually work for as long as you give them, and that is true of most medical interventions, for diabetes or for congestive heart disease, mostly for all chronic diseases.

2. There is conflicting evidence. Evidence I have read suggests that stimulant-treatment in young age, improves structural improvement in the ADHD-inflicted brain, and reduces severity of ADHD symptoms if drug is withdrawn in adolescence. Others may need to be on Ritalin/Adderall for the rest of their lives.

3. There is a huge amount of clinical evidence that suggests that ADHD medications work long-term.



They found that the level of DAT in patients with ADHD was strongly linked to whether patients had received long-term medication or not. Patients who had never taken stimulant medication had abnormally reduced DAT levels in their brain, whilst patients who had received long-term medication had abnormally elevated DAT levels.


Sure, but what else happens?

Other good stuff such as (cf. http://www.ncbi.nlm....pubmed/21956611):



Both adolescent MPH exposure and DAT-targeting transfection lead to enduring hyperfunction of dorsal striatum and hypofunction of ventral striatum. Together with upregulation of prefronto-cortical phospho-creatine, striatal upregulation of selected genes (like serotonin 7 receptor gene) suggests that enhanced inhibitory control is generated by adolescent MPH exposure.


Not to mention that methylphenidate is neuro-protective
(cf. http://www.ncbi.nlm....pubmed/19587858)



As delineated in this review, the neuroprotective effects of methylphenidate are due, at least in part, to its ability to attenuate or prevent this abnormal cytoplasmic dopamine accumulation through several possible neuropharmacological mechanisms. These may include 1) direct interactions between methylphenidate and the neuronal dopamine transporter which may attenuate or prevent the entry of methamphetamine into dopaminergic neurons and may also decrease the synthesis of cytoplasmic dopamine through a D2 receptor-mediated signal cascade process, and 2) indirect effects upon the functioning of the vesicular monoamine transporter-2 which may increase vesicular dopamine sequestration through both vesicle trafficking and the kinetic upregulation of the vesicular monoamine transporter-2 protein.





The findings suggest that, when treated with stimulants, the brain adapts to compensate for the high levels of dopamine by building up more DATs to eliminate the abnormally high levels of dopamine. The findings therefore show that increased DAT levels in ADHD is a consequence of long-term medication rather than the disorder itself.


Interesting, because here they find a decrease in DATs
(cf. http://www.ncbi.nlm....bmed/12776228):



Adults suffering from Attention Deficit Hyperactivity Disorder (ADHD) are known to have disturbed central dopaminergic transmission. With Single Photon Emission Computed Tomography (SPECT) we studied braindopamine transporter and receptor activity in six boys with ADHD. Three months after initiation of treatment with

methylphenidate we found a down-regulation of the post-synaptic dopamine receptor with a maximum of 20 % and a down-regulation of the dopamine transporter with a maximum of 74.7 % in the striatal system. This corresponded to a positive clinical response evaluated by neuropsychological questionnaires and tests. We suggest that dopamine transporter imaging by SPECT might be used to monitor psychostimulant treatment in children suffering from ADHD.


Even the authors of the original paper, seem a bit perplexed as well, and are not necessarily entirely certain about the results, and are hesitant about inferring causality, without more and randomized quality research about the long-term adaptation and even its clinical relevance.

From the FT:

However, the effect size was small and heterogeneity across studies was substantial, with a prominent effect of psychostimulant history on the findings, accounting for a substantial proportion of variance across studies.


A caveat is that these findings are from cross-sectional analyses, with a selection bias, and we therefore cannot infer direct causality.


The present study has several limitations. The meta-regression finding of an association between medication and dopamine transporter density is limited by the cross-sectional nature of the analysis, and causality of the regression findings needs to be established in longitudinal prospective studies using a randomized controlled design. It has been suggested that high heterogeneity across studies may be due to differing dopamine transporter sensitivity across the different radiotracers employed. For example, there is evidence that the specific-to-nonspecific ratio of labeled cocaine is relatively low and that this radioligand may occupy binding sites other than those occupied by FP-CIT, altropane, TRODAT-1, and IPT (57). Furthermore, dopamine transporter binding may be influenced by a complex network of interactions with other receptors or neurotransmitters.


For example, there is recent evidence that norepi-nephrine transporters contribute to the pathophysiologyof ADHD, with norepinephrine transporter blockade infrontal regions underlying some of the therapeutic effectsof methylphenidate (58). However, while methylphenidateenhances both norepinephrine and dopamine in pre-frontal brain regions, where it blocks both the relativelydensely distributed norepinephrine transporters and theless densely distributed dopamine transporters (58), inthe basal ganglia methylphenidate has minimal effects onnorepinephrine levels, since the norepinephrine trans-porter density is vanishingly low (6). Other studies havefound that presynaptic Dﰀ autoreceptor activation, nor-mally constraining dopamine action at synapses, regulatesdopamine transporter activity that modulates synapticdopamine homeostasis (59). The picture is further com-plicated by a potential interplay between dopamine trans-porter functioning and nicotinic neurotransmission atthe presynaptic level (60). Finally, there is recent evidencesuggesting that the ADHD diagnostic category comprisesmultiple entities with different underlying pathophysiologies and abnormalities of neurotransmitter profiles (61). Inparticular, children with the combined/hyperactive sub-type of ADHD show a higher frequency of conduct disor-der and good response to treatment, are exposed to moremoderate stress during their mothers’ pregnancies, andhave a higher frequency of the L genotype for a polymor-phic region of the serotonin transporter gene, as comparedto children with the inattentive ADHD subtype (61). On thebasis of animal studies showing dopamine transporter dif-ferences in the pathophysiology of the two subtypes, it ispossible to speculate that treatment with methylphenidatemight normalize abnormal dopamine transporter levelsmore effectively in the combined subtype (62).


Clearly, as you can see, a mixed picture.

Edited by kassem23, 07 February 2012 - 05:41 AM.


#11 InquilineKea

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Posted 07 February 2012 - 10:56 PM

I am aware of hysteresis as there has been many, many examples and cases written about it in science/medical journals -- it's why I mentioned normal people would probably adjust to the alien environment faster than that of an ADHD sufferer [rise in DA levels, body initiates mechanisms to ameliorate deviation from equilibrium; if a hysteresis loop occurs, it is highly possible there will be a mechanism to normalize its effects; it would take longer for ADHD sufferers because their initial DA levels are lowered and will take longer to have the stimulant's modulation effects summate to initialize said mechanisms]. With that said, I don't want to delude myself or anybody reading my posts into thinking I am an expert in this particular realm of physical science -- but I did account for it when I wrote my response. The thing with hysteresis arising in biological systems is that the human body is very smart in how it deals with these fundamental thermodynamic changes that promotes undesirable shifts in the homeostatic equilibrium. Sparkk51's analogy is pretty solid for what I'm trying to explain; sure, with elevated DA levels in the brain due to exogenous means may generate a bio-molecular hysteresis-like system loop to sustain the new environment, but you shouldn't assume the body doesn't have compensatory mechanisms in place to recreate initial conditions. Biological/bio-chemical systems tend to have mechanisms that either prevent or to compensate for such loops to occur: a simple example would be cell apoptosis; a complex example is the proposed role of non-coding DNA in regulation and modification of the human genome. From what I see, the only way for an individual to experience an irreversible change [meaning living chronically with new homeostatic equilibrium] such as this AFTER ceasing the medication that resulted in the new environment, two things need to occur: first, have irreversible agonists of dopaminergic cells or antagonists of DA re-uptakers to initiate the shift in equilibrium; second the new cellular environment needs to be able to generate genomic changes so that either the irreversible agonist/antagonist bound cellular/compound modalities affected are left alone [does not get broken down/go through apoptosis] -- this goes into the realms of cancer, or somehow alter coding sequences for these affected cellular/compound modalities so that they will be able to sustain the new environment after the original affected cellular/compound modalities have been purged from the system. Of course, all of this can happen but it is unlikely.


The human body is very smart in dealing with certain thermodynamic changes that promote these undesirable shifts, but that doesn't mean that it's very smart in dealing with other such thermodynamic changes. As one example - aging is the perfect example of one shift in the equilibrium that the body ultimately fails to deal with (and horrifically so). As another example - metabolic syndrome. Both of these are effectively irreversible.

I do appreciate your examples though - they are illuminating, and I hope they are true. I just fear that they may not be true for this situation. In any case, there is one study that does imply that DAT receptor upregulation is reversible.

#12 InquilineKea

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Posted 07 February 2012 - 11:01 PM

kassem23 - I do hope that you're right. But I do fear that you might not be right for all people.

Anecdotally, it does seem to be the case that some people are fine with medication (and get no tolerance), whereas others develop tolerance to it and then need to develop breaks. The thing is - how are we going to identify which people will develop tolerance, and which don't develop tolerance?

Neurotoxicity/neuroprotectivity is unrelated with this (upregulation/downregulation is neutral to the issue of toxicity - though there may be indirect effects)

#13 Reformed-Redan

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Posted 04 July 2017 - 08:36 PM

In regards to methylphenidate use and DAT upregulation, this only seems to be an issue with high levels of MPH use and different ROA's than oral and use above therapeutic levels.

 

One upside of DAT level elevation is increased potency and effects from releasing agents as per the study below. 

 

So, basically, if you keep your doses therapeutic and don't abuse MPH, then everything should be fine. Alternatively, if MPH no longer works as intended due to an individual characteristic or abuse liability, then AMPH can be used to negate the upregulation of DAT levels.

 

So, just cycle between MPH and AMPH is what I would do.

 

https://www.ncbi.nlm...PMC4017736/#R15



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#14 Reformed-Redan

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Posted 04 July 2017 - 08:43 PM

Basically, you can exploit the upregulation in DAT levels if you have ADHD or moreso ADD-PI by cycling through MPH and AMPH.

 

And, I haven't seen evidence showing that the DAT upregulation is irreversible. 







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