View Full Version : Dopamine Beta Hydroxylase Antibodies could this hypothetically cure ADHD?


InvitroCanibal
02-10-14, 04:51 PM
http://ghr.nlm.nih.gov/gene/DBH

The DBH gene is responsible for converting dopamine to neuroepinephrine. Alterations in the gene result in a neuroepinephrine deficiency in the body as well as possibly too much dopamine, this is indicated in schizophrenics and certain mood disorders, it may also be related to inattentive add but I am unsure just how much dopamine plays a role in inattentive add as more research I've read seems to indicate Acetylcholine and Ach esterase relationship to ADD pi.

Too much DBH equals a lack of dopamine in the system which results in too much neuroepinephrine which can equal Hyperactivity unless neuro epinephrine is boosted high enough to reach the Alpha Agonist receptors=possible cause for calming effects of stimulants in adhd or increased dopamine/d2 receptor agonism.




http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2626918/

This research summary on adhd mentions all the possible theories on ADHD and the neuroscience behind it. It's worth reading irregardless of what i'm theorizing.

The reason I showed the article in spite of it mentioning DBH is that it mentions a specific relationship imbalance between doapamine and neuroepinephrine in the frontal lobes. It also mentions that ADHD sufferers are under constant stress. How can this be and there be a lack of neuroepinephrine. Also why is strattera consider useless in most cases? I believe that having too much DBH is actually the cause of ADHD in that too much neuro epinephrine is being produced and therefore the brain is starved of dopamine.

I'm by no means suggesting anyone go out and purchase DBH antibodies, I just simply wanted to post that a DBH reducer does infact exist. However the implications of too little DBH can equal a neuroepinephrine deficiency. I believe there is a relationship between this and chronic fatigue syndrome which some claim to have.

Finally, I apologize if I'm way off in this post or I completely missed the forest for the trees. It's why I posted so that if I am wrong or way off, that maybe someone can enlighten me?

dvdnvwls
02-10-14, 04:58 PM
To create a cure for ADHD, first we would need to know (as opposed to having a hunch about) its cause.

InvitroCanibal
02-10-14, 05:12 PM
To create a cure for ADHD, first we would need to know (as opposed to having a hunch about) its cause.

Neurotransmitters

Dopamine-Regulating Genes in ADHD

Early adverse stress trauma environments are implicated in ADHD over national boundaries [122–124]. Deprivation in social and environmental conditions may perturb early cellular patterns of neurodevelopment that are manifested as disorder expression in later life [125], with aspects of ADHD originating in early deprivation [126,127]. Epigenetic factors have implicated both dopamine and serotonin in ADHD symptoms, particularly impulsive behaviors. For example, functional gene variants in the serotonin transporter gene-linked polymorphic region 5-HTTLPR are implicated in neural mechanisms of disorders relating to impulsive control [128,129]. Moreover, candidate gene studies in ADHD children have had a predominating focus upon the monoaminergic neurotransmitter systems with particular attention on dopamine and the major focus upon DAT1 and the DRDs dopamine receptor genes. Early institutional deprivation with ADHD as outcome [130] was shown to vary greatly over individuals despite high levels of adversity [131]. Perinatal environmental risk is moderated by genetic factors in determining outcome [132,133]. The DAT1 (SLC6A3) transport and DRD4 receptor genes are implicated in the pathophysiology of ADHD [83,134,135]. Stevens et al. [136] examined the moderating effect of DRD4 and DAT1 functional polymorphisms on deprivational influences following institutionalization upon ADHD in a longitudinal study with participants at ages 6, 11, and 15 years-of-age. This type of study would ensure both a proper establishment of a G E hypothesis, and a test of developmental G E mechanisms. The investigators observed that the early institutional-deprivation as an ADHD risk factor was moderated by the DAT1 but not the DRD4 genotype. These effects appeared first in early-adolescence and persisted to mild-adolescence, which was their ultimate period of analysis. The authors concluded that the results: (a) provided evidence for developmental continuities in the G E interaction, (b) explained part of the heterogeneity in ADHD outcomes following institutional deprivation, and (c) further contribute to understanding of environmental determinants of ADHD in the institutional setting. In a broader perspective, their findings provide an essential description of the developmental trajectories to be defined in developmental disorder.

Following the initial report by Comings et al. [137] of Taq A1 allele association in ADHD individuals, and as Blum et al. [74] have reviewed, both positive and negative findings related to the putative association of DRD2 A1 allele as a critical gene polymorphic link to ADHD and related behaviors are documented (see also [138,139]). Plausible evidence for the ADHD association is derived from a number of studies. For example, Sery et al. [140] obtained statistically different genotypic and allelic frequencies of DRD2 polymorphism between the two groups of boys that they studied. Similarly, Kopeckova et al. [88] observed that ADHD-risk (a) was linked to a risk allele in DRD2 gene, the 5-HTT gene, and the DAT1 gene, (b) was elevated at homozygotes for risk alleles in the same genes and for polymorphisms G444A and C1603T in dopamine-β-hydroxylase (DBH), and (c) was increased in the presence of allele DBH +444A and allele DBH +1603T. More recently, Paclt et al. [141] studied a sample of 269 ADHD boys and a control group of 317 boys. Comparison of genotype frequencies indicated a highly significant difference between the two groups, with the A1 allele having a 4.359-fold higher risk for ADHD. Within the context of association studies focused upon endophenotype, Esposito-Smythers et al. [142] found interaction effects between the DRD2 TaqIA polymorphism and CD, also between A1+ status and impulsiveness, whereby adolescent carriers of the A1 allele with CD or impulsiveness, reported higher levels of problematic alcohol use than non-carriers (A2/A2 or A1−). They obtained the same interaction effect between impulsiveness and DRD2 TaqIA polymorphism regarding severity of problem drug use. However, no interaction effects were obtained between the DRD2 allele status and ADHD on severity of problem drinking or drug use. Blum et al. [74] discussed the viability of ADHD genetic testing at birth with obvious diagnostic benefits probable via: (a) coupling of genotyping with psychometric instruments, (b) that dopaminergic genotyping to determine high risk future substance abuse may affect use in adolescents, and (c) applications of D2 agonists for ADHD symptoms related to specific candidate polymorphisms. Following several independent meta-analyses confirming the association of DRD2 polymorphisms with impulsive-additive-compulsive behaviors that include ADHD symptoms, Blum et al. [143,144] coined the notion of “Reward Deficiency Syndrome” implicating dopamine D2 gene variants (see also [145–147]).
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3250517/ --this link is from the one above. I figured I'd requote it and take out what I was referring to.

http://www.ncbi.nlm.nih.gov/books/NBK1474/

It's more than a hunch, sorry I left out this pub med article. It mentions polymorphisms in the genes responisble fpr regulating DBH related to multiple disorders. Including but not limited to ADHD. Also it proposes possible tests in which DBH enzyme levels could be observed and measured.

Thanks

TygerSan
02-11-14, 07:49 AM
Not to put a crimp in your plan, but the anti-dbh antibody has to attach to something that actually reduces dopamine beta hydroxylase. Usually it's attached to a ribosomal toxin saporin. If the two are paired, the dbh molecule is recognized like a key and the toxin is let into the noradrenaline neuron, killing it. That is, the effect is irreversible, unlike drugs. It's also something that doesn't readily cross the blood brain barrier, so you'd have to find a delivery method to get it to the correct area of the brain.

How do I know this? I've used the antibody in a research study on rodents, injecting the toxin into specific areas of the brain.

I'm not saying that you don't have a good idea, just that technology and ability to test it clinically aren't quite there yet.

TygerSan
02-11-14, 08:20 AM
Also, there are alternative synthesis pathways that can bypass a lack of DBH and still produce norepinephrine. Nature is full of redudancy. This is why simply taking something like sinamet (a dopamine agonist that just increases the amount of dopamine made by a given neuron) doesn't help in ADHD like it does in Parkinson's.

In Parkinson's, there are so few dopamine neurons left that increasing the amount of dopamine in the synapse really has a profound impact on function. In ADHD where the scenario is a bit more complicated than a global dopamine deficiency, increasing the amount of dopamine in the synapse directly triggers all sorts of compensatory mechanisms that decrease the amount of dopamine the neurons crank out, thereby limiting the effect of the dopamine boost. Stimulants, on the other hand, increase the availability of the dopamine the neurons have already produced, which seems to be more effective.

Going back to your original idea, may I also offer this for food for thought: dopamine and norepinephrine are incredibly close cousins. You know how if you have a poorly cut key, you can kind of wiggle and jiggle a lock and open it with a poor match? Dopamine fits the norepinephrine receptor like that poorly cut key and vice versa. It is almost impossible to impact the dopamine system without impacting the norepinephrine system and vice versa.

The funny thing is that pharmacologists keep trying to make these really specific drugs that target A but not B ....and for the most part these drugs wind up being great research tools. When it comes to therapeutic efficacy, however, the less specific drugs seem to do better.

InvitroCanibal
02-11-14, 04:04 PM
Also, there are alternative synthesis pathways that can bypass a lack of DBH and still produce norepinephrine. Nature is full of redudancy. This is why simply taking something like sinamet (a dopamine agonist that just increases the amount of dopamine made by a given neuron) doesn't help in ADHD like it does in Parkinson's.

In Parkinson's, there are so few dopamine neurons left that increasing the amount of dopamine in the synapse really has a profound impact on function. In ADHD where the scenario is a bit more complicated than a global dopamine deficiency, increasing the amount of dopamine in the synapse directly triggers all sorts of compensatory mechanisms that decrease the amount of dopamine the neurons crank out, thereby limiting the effect of the dopamine boost. Stimulants, on the other hand, increase the availability of the dopamine the neurons have already produced, which seems to be more effective.

Going back to your original idea, may I also offer this for food for thought: dopamine and norepinephrine are incredibly close cousins. You know how if you have a poorly cut key, you can kind of wiggle and jiggle a lock and open it with a poor match? Dopamine fits the norepinephrine receptor like that poorly cut key and vice versa. It is almost impossible to impact the dopamine system without impacting the norepinephrine system and vice versa.

The funny thing is that pharmacologists keep trying to make these really specific drugs that target A but not B ....and for the most part these drugs wind up being great research tools. When it comes to therapeutic efficacy, however, the less specific drugs seem to do better.

I appreciate your response, I'll keep looking into it. I forgot that any kind of antibody doesn't cross the blood brain barrier.

Also I am aware of this interchangeable relationship between dopamine and neuroepinephrine. I was looking at DBH deficiency syndrome and wondered if ADHD occured in the opposite way. The syndrome is marked by too much dopamine which takes the place of neuroepinephrine and causes droopy eyelids, and a host of other issues.

When I looked into my theory/hypothesis/guess, I found that there was indeed a relationship there. Though I know that antibodies are not an option, I looked into it a bit more and found out that Nicotine seems to affect DBH and TH directly.

http://www.ncbi.nlm.nih.gov/pubmed/7901211

http://books.google.com/books?id=sNQ7IA3y2kAC&pg=PA54&lpg=PA54&dq=nicotine%27s+effect+on+DBH&source=bl&ots=IWZ2zK5liQ&sig=Lw8eTTxqueRPTc1tmEEjxK97qMM&hl=en&sa=X&ei=NHz6UrSJBMSuyQG8p4HgDA&ved=0CE0Q6AEwBA#v=onepage&q=nicotine%27s%20effect%20on%20DBH&f=false

That weird link above is to a book called "catecholamines:briding basic science with clinical medicines"

It shows that there is indeed a relationship between TH gene expression and DBH expression. Nicotine seems to stimulate TH long term. This means a direct increase in dopamine synthesis inspite of the break down of dopamine at faster rates if DBH were present at higher levels.

Though I understand the interchangeability of dopamine to neuroepinephrine it seems like they still have seperate effects between each other inspite of being able to stimulate the same pathways. This kind of explains why Strattera didn't work too well. It was based on the idea that neuroepinephrine could directly take the place of dopamine and that would work for adhd people.

http://books.google.com/books?id=Wkv85Uvi6uYC&pg=PA265&lpg=PA265&dq=nicotine%27s+effect+on+DBH&source=bl&ots=jn3r6V5gE3&sig=diJE6DjubeudpH2FenBKLFUpgEM&hl=en&sa=X&ei=1376Uuu9D4nIyAHknoCoBA&ved=0CFQQ6AEwBg#v=onepage&q=nicotine%27s%20effect%20on%20DBH&f=false

Furthermore, the success rate of Welbutrin to stimulate the reward pathways in people with increased gene expression of Tyrosine Hydroxylase was higher than those who lacked this variant. Smokers tend to self medicate and thats what the above link also shows is that tendency but it doesn't relate this all to adhd.

However when you consider that a statistically higher number of smokers are ADHD, it may in fact be relaying the information that those with less available dopamine or those with adhd were unable to quit effectively.

So one could go about this in two different ways, either boost the TH expression or decrease DBH expression. Nicotine as we know already seems to boost TH expression long term. Now what doesn't add up is why then is quitting so difficult for those with ADHD?

I think that it actually does do something long term that benefits those with ADHD but it may in fact produce better results from permenant Nicotine replacement therapy.

Many studies now seem to also point to this that long term BENEFITS actually exist with nicotine replacement therapy. Reduced Parkinsons disease rates is one of them.

So my question is then, is Nicotine a possible long term benefit for ADHD people and could this effect be exploited in a similar but different drug?

I do understand what you are saying though in terms of, it's not a one size fits all solution but if it could help say 30 percent of those with ADHD it seems like it'd be worth it. Though I recognize that a placebo is 30 percent as well lol but I think that if the effects were permenant and a cure for 30 percent that would be different than a placebo.

TygerSan
02-11-14, 04:29 PM
So my question is then, is Nicotine a possible long term benefit for ADHD people and could this effect be exploited in a similar but different drug?

:)

That's a question that's near and dear to my heart. It's the one that started me down the path towards a research degree. You've got some great questions, and ones that would be really interesting to investigate in a research setting.

With regards to nicotine, there are drugs in the pipeline, and this research group (Potter and Newhouse specifically) have shown that drugs that affect the nicotinic receptor do show some therapeutic benefit. http://www.ncbi.nlm.nih.gov/pubmed/23856296
http://www.nature.com/npp/journal/v38/n3/abs/npp2012194a.html

Conman
02-14-14, 05:51 PM
i dont think anybody has noted it, but it's Norepinephrine not neuroepinephrine. and an excess of Norepinephrine would be the equivalent of a powerful stimulant, producing associated effects like rapid heartbeat, high blood pressure, dizziness, nausea, headaches, etc.

what i do know is that while genetically AD/HD has alot of associations with (or full-blown caused by if you take the purely genetic/biological route) the Dopamine system, but it's also only partially due to lower Dopamine. in general from what ive read it seems it's not just low Dopamine but in abnormalities of how the Dopamine system responds to stimulation (low Dopamine is a way it can respond to stimulation, or lack thereof).

there also appears to be abnormalities with the Serotonergic and apparently Cholinergic systems as well. i dont know about the Cholinergic one but ive always heard the main 3 abnormalities of neurotransmitters in AD/HD were Dopamine, Serotonin and Norepinephrine. Norepinephrine is important in forming memories, so potentially a deficiency in some receptors for that is possible. Serotonin...i think it's easy enough to say whatever's wrong with that system can cause all sorts of effects.

somebody correct me or enlighten me if anything i said is incorrect, im just going off the things ive read or have learned in the few instances AD/HD got talked about in Psych classes and what ive learned of neurotransmitters.