Teach me about Dopamine

[LNN]

 

So... The problem with D1 and D2 receptors is that it seems that the antibodies in our kid's blood serum is locking into these receptors. So.. the the quote from the letter "Antibodies may induce increased signaling of neuronal cells and cause release of too much dopamine in the brain." indicates that we may have too much dopamine as a result of all of this.

 

I hope that makes sense and is not more confusing!

 

So...if the receptor is blocked because an auto-antibody has shoved its way into the receptor, it prevents that receptor from re-uptaking the dopamine puddled up in the cleft. Does this cause neuronal signalling from the blocked receptor (I'll call him Al)? Al says "Hey Bob, send more dopamine - I'm not getting enough!" So Bob, the sending dendrite, sends more dopamine. The cleft puddle gets bigger. (thus, too much dopamine).

But...Al still shows symptoms of too little dopamine. He's not getting what Bob is sending. Can you then have too much dopamine outside the neuron and too little inside? It would then become a balance problem (within vs. outside of the neuron) rather than too little or too much in the overall system?

 

Because as Jill said, I swear my son looks like too little dopamine. (FWIW - neither of his D measurements were out of range yet he ticced severely). The attention deficits clearly get in the way of academics, even when in remission.

 

And then I have the question of the state of affairs when not in a flare. As Jill asked earlier, can you have a general state of low dopamine when in remission that would benefit from tyrosine or amatadine or something that boosts dopamine re-uptake?

Edited February 22, 2013 by LLM

[3boysmom]

The confussing thing for me is that DS13 had very high D2 and DS10 had very low D2 and were both having issues (although different issues) both PANDAS. Well now I believe that DS13 has moved into the PANS category with the last flare coming from a virus and not strep. I JUST WANT SOME FOCUS for this kid. Holy cow, he is SOOOOOOO SLOW! I am at the point of just giving anything a try and praying for the best.....is that wrong?

[JAG10]

I don't think that's wrong.

I think Laura's questions are spot on; ditto.

 

 

[JAG10]

I found this summary that explained that there are two different dopamines (I'm guessing d1 and d2). So it's not a see-saw, but more independent.

Dopamine: Parkinson’s Disease and ADHD to Smoking and ParanoiaDopamine is a neurotransmitter linked to motor/movement disorders, ADHD, addictions, paranoia, and schizophrenia. Dopamine strongly influences both motor and thinking areas of the brain.

 

One type of Dopamine works in the brain movement and motor system. As this level of dopamine decreases below the “normal range” we begin to experience more motor and gross-movement problems. Very low levels of Dopamine in the motor areas of the brain are known to produce Parkinson’s Disease with symptoms such as:

 

• Muscle rigidity and stiffness
• Stooped/unstable posture
• Loss of balance and coordination
• Gait (walking pattern) disturbance
• Slow movements and difficulty with voluntary movements
• Small-step gait/walking
• Aches in muscles
• Tremors and shaking
• Fixed, mask-like facial expression
• Slow, monotone speech
• Impairment of fine-motor skills
• Falling when walking
• Impairment in cognitive/intellectual ability

Dopamine in the thinking areas of the brain might be considered the neurotransmitter of focus and attending. Low levels impair our ability to focus on our environment or to “lock on” to tasks, activities, or conversations. Low levels of Dopamine make concentration and focus very difficult with low levels also associated with Attention-Deficit Hyperactivity Disorder (ADHD). On the other end of the Dopamine dipstick, as Dopamine levels in the brain begin to raise, we become excited/energized, then suspicious and paranoid, then finally hyperstimulated by our environment. With low levels of Dopamine, we can’t focus while with high levels of Dopamine our focus becomes narrowed and intense to the point of focusing on everything in our environment as though it were directly related to our situation.

 

Mild elevations in Dopamine are associated with addictions. Nicotine, cocaine, and other substances produce a feeling of excited euphoria by increasing Dopamine levels in the brain. Too much of these chemicals/substances and we feel “wired” as moderate levels of Dopamine make us hyperstimulated – paying too much attention to our environment due to being overstimulated and unable to separate what’s important and what is not.

 

In an ADHD child, low levels of Dopamine don’t allow the child to focus or attend to anything in the environment, looking very physically hyperactive when running about the room or switching from activity-to-activity due to their lack of focus. As Dopamine levels increase above the normal range, our ability to focus increases to the point of being paranoid. Mild elevations make the environment overly stimulating and excited.

 

Moderately high Dopamine levels make us on-guard, suspicious, and prone to misinterpret experiences in the environment. Known as an “idea of reference” in psychiatry, we begin thinking unrelated experiences are suddenly directly related to us. People observed talking across the street are now talking about us. As Dopamine increases, it can become so intense that we feel the radio, television, and newspaper contain secret messages directed at us from Hollywood or elsewhere. It’s as though we are attempting to incorporate/add everything we witness into our life. Planes flying overhead are snapping pictures of us and motorists talking on cellular phones are calling in a report on us. Our mind speed increases and races in an attempt to add all we see into our life. In an attempt to make sense, we may become extremely religious, paranoid, or feel we are a very important person. Increased Dopamine also increases the perception of our senses, as though turning up the volume in all our senses – hearing, vision, taste, smell, and touch.

 

As Dopamine levels increase, the noises we heard loudly suddenly become auditory hallucinations. Our inner thoughts are now being heard outside our body. These “voices” begin talking to us, known to take different forms such as derogatory (putting you down), religious topics, command (telling you to do something), or sexual content. Hallucinations (experiencing something that is not truly there in reality) will soon develop in all our senses. We may begin seeing faces in clouds, carpets, or patterns. We may sense the touch of spirits or movements inside our body. We may experience unusual smells or tastes.

 

High levels of Dopamine in the brain often cause us to lose our contact with reality. As though living in a science-fiction movie, we begin to develop unusual if not bizarre ideas about what is happening to us. With our paranoia, we may experience delusions (false beliefs) of persecution or may think we have super powers (delusions of grandiosity) and can predict the future or read minds. High levels of Dopamine are found in Schizophrenia, drug intoxication, and other psychotic conditions where the ability to distinguish the inner world from the real world is impaired.

 

Treatment for psychiatric/medical conditions associated with Dopamine imbalance, as you might expect, involves increasing or decreasing Dopamine levels in the brain. Low-Dopamine disorders are treated with medications that increase Dopamine in the brain. For Parkinson’s Disease – L Dopa is prescribed and for ADHD, medications that are psychostimulants. Amphetamines and medications with similar action actually slow down the hyperactive (ADHD) children by increasing Dopamine – boasting their level into the normal range, allowing them to now focus and attend.

 

Mildly elevations in Dopamine are associated with addictions such as narcotics, speed, and nicotine/smoking.Thus, medications used in the treatment of addictions actually block or lower Dopamine production. If a medication blocks dopamine, it also blocks the effects of the addicted substance as well as blocking the craving sensation. The medication to help smokers, Zyban, is actually the antidepressant Wellbutrin that is known to block Dopamine.

 

Moderate to high levels of Dopamine, associated with severe psychiatric conditions such as Paranoia and Schizophrenia, are treated with medications that block or lower Dopamine in the brain. These medications, called antipsychotics, have been available for many years. Early antipsychotic medications however, lowered Dopamine throughout the brain, including the Dopamine located in the motor/movement areas. For that reason, older antipsychotic medications produced motor/movement problems that looked like Parkinson’s Disease – short-step gait, fixed facial expression, tremors, poor balance, etc. Newer medications have fewer side effects in motor areas, as they are able to specifically target one type of Dopamine.

 

Dopamine levels typically change very slowly. Patients who develop Paranoia and/or Schizophrenia often experience a gradual increase in Dopamine levels over several years – also experiencing an increase in the severity of symptoms over those years. A typical high school or college student may develop a sense of being on-edge or unusual feelings, gradually becoming suspicious and feeling alienated, moving into auditory hallucinations, and finally developing bizarre false beliefs (delusions) of persecution or exaggerated self-importance over the next several years. Stress can often rapidly increase Dopamine, but it still rarely happens overnight.

 

When an individual becomes psychotic, paranoid, and hallucinates in only a few days, we must strongly suspect medication/drug intoxication or neurological events – something that could increase Dopamine levels dramatically and almost instantly. The prolonged use of amphetamines (speed) or steroids can produce a loss of reality and sudden paranoia. As it might happen, a construction worker taking “street” speed to increase his work productivity finds his hand or foot talking to him (auditory hallucinations) and decides to cut it off. The sudden presence of psychosis (hallucinations, delusions, paranoia, etc.) in an individual with a history of prior normal adjustment would suggest the need for intensive medical and neurological workup.

 

 

[3boysmom]

Wow, very helpful and kind of scary. So, what to do, what to do ?

[JAG10]

But still doesn't help with the whole "blockage" versus production question...... Or what to do about it. Wonder if its a low n slow scenario with Amantadine?

[LNN]

Well, it certainly puts a more favorable light on ADHD meds. So often, I hear it slammed - "I'm not going to give my kid a stimulant!" - but if you frame it as "I'm going to give my kid something to help raise his dopamine into a normal range" - same drug but a completely different spin, eh?

 

And while I still lean toward DS being low dopamine (motor issues, attention issues), there is a history of family addiction and let's not overlook video game addiction (not that anyone here has ever had to deal with that)

 

Finally, to further complicate JAG's last question of recptor blockage vs. overproduction, while the cleft puddle is busy filling up with "excess" dopamine, neurotransmitters "oxidize: while in that cleft (i.e. they "rust" and degrade and become unusable/non-recyclable) over time. That's why when you take an anti-depressant for a long time, it "poops out" and stops working. Unless you put new dopamine into the system, you eventually run too low on dopamine and no matter how much you increase your anti-depressant dosage, it stops working. So you do the long (6 week) process of tapering off and the the long process (6 weeks ) of starting a new anti-depressant. The whole time, you're contributing to oxidative stress and cell damage while the raw material (dopamine) puddles instead of being re-uptaked (?) by my friend Al.

 

Great discussion. Now someone tell me what to do!

[powerofprayer]

I thought tics are thought to be a result of too much dopamine, not too little? I am referring to TS tics though so maybe theres a difference depending on the condition causing the tics. Now I'm really confused.

[trggirl]

Powerofprayer, you are right. Dopamine is said to contribute to TS tics.

 

I personally think that in some cases of tics you have to look at the Camkinase II level as well. At some point I have either read or some doc has said that high CamK kids are usually ticcer kids. I suspect when someone figures out what mechanism is going on with that high CamK, they will figure out what is causing some cases of tics.

[kimballot]

 

So... The problem with D1 and D2 receptors is that it seems that the antibodies in our kid's blood serum is locking into these receptors. So.. the the quote from the letter "Antibodies may induce increased signaling of neuronal cells and cause release of too much dopamine in the brain." indicates that we may have too much dopamine as a result of all of this.

 

I hope that makes sense and is not more confusing!

 

So...if the receptor is blocked because an auto-antibody has shoved its way into the receptor, it prevents that receptor from re-uptaking the dopamine puddled up in the cleft. Does this cause neuronal signalling from the blocked receptor (I'll call him Al)? Al says "Hey Bob, send more dopamine - I'm not getting enough!" So Bob, the sending dendrite, sends more dopamine. The cleft puddle gets bigger. (thus, too much dopamine).

But...Al still shows symptoms of too little dopamine. He's not getting what Bob is sending. Can you then have too much dopamine outside the neuron and too little inside? It would then become a balance problem (within vs. outside of the neuron) rather than too little or too much in the overall system?

 

Because as Jill said, I swear my son looks like too little dopamine. (FWIW - neither of his D measurements were out of range yet he ticced severely). The attention deficits clearly get in the way of academics, even when in remission.

 

And then I have the question of the state of affairs when not in a flare. As Jill asked earlier, can you have a general state of low dopamine when in remission that would benefit from tyrosine or amatadine or something that boosts dopamine re-uptake?

 

Not exactly - From my understanding, if an antibody binds with the receptor it does not necessarily block the receptor. The antibody could act as an agonist and actually turn the receptor on... in that case it is mimicking the neurotransmitter. If it is binding with a neuron that produces Cam Kinase, it will produce more Cam Kinase.. which does many things, including help to manufacture dopamine. If the antibody is binding with a dopamine receptor and is acting as an agonist it is turning on the dopamine receptor. The neuron thinks it is getting dopamine and will act as if it had dopamine. The neuron will then do whatever it is designed to do when it receives dopamine.. and that depends on where the neuron is located. That is why changes in dopamine levels in the basal ganglia look different from changes in the dopamine levels in the frontal lobe or the limbic system. D1 receptors and D2 receptors tend to be located in different parts of the brain. This may help http://www.livestrong.com/article/141471-5-types-dopamine-receptors/ . So.. the problem, I think, is more WHERE the antibodies are attacking the brain - more than whether the dopamine is going up or down. I think that is why some of us see more emotional changes (limibic / D1), some see more ADHD symptoms (cortex / D1) and some see more movement (Basal ganglia / D2), and some times we get real lucky (sarcasm) and see it all.

 

We also have to remember that all of this is theory right now. They are learning from our kids. In reality, this is probably a very simplistic model and is only a piece of what is going on. Many people think that cytokines and other immune responses also play a huge role in what is happening with our kids - hence the relationship to inflammation. Also, just because your child's antibodies tended to "turn on" D1, D2, or cam kinase, does not mean that those antibodies are currently in your child's brain. Antibodies are not supposed to be in brains. They cross the blood-brain barrier with infection or inflammation. It just means that if they did cross, then your child has more of a likelihood that this binding would occur than some child without aoutoimmune tendencies.

Edited February 22, 2013 by kimballot

[kimballot]

OK, I am home now and pulling out the huge binder of tests and notes and labs from the 3 boys over these 3 years!!!

Cunningham tests run 10-25-2010:

 

DS13 (then 10-almost 11)-Huge overnight dysfunctional OCD and body movements (NO TICS at the time)

Cam Kinase II score: 166

Anti-Lysoganglioside: 160 (normal range: 80-320)

Anti-Tubulin: 1000 (normal range: 250-1000)

Anti-Dopamine 1: 1000 (normal range: 500-2000)

Anti-Dopamine 2: 16000 (normal range: 2000-16000) VERY HIGH

 

DS11 (then 9)-night terrors, baby talk, personality change, HSP (No OCD & No tics)

Cam Kinase II score: 140

Anti-Lysoganglioside: 160 (normal range: 80-320)

Anti-Tubulin: 500 (normal range: 250-1000)

Anti-Dopamine 1: 2000 (normal range: 500-2000) HIGH

Anti-Dopamine 2: 8000 (normal range: 2000-16000)

 

DS10 (then 7)- Hyper, impulsive, immature, anxiety, and vocal & head tics (NO OCD):

Cam Kinase II score: 134

Anti-Lysoganglioside: 160 (normal range: 80-320)

Anti-Tubulin: 500 (normal range: 250-1000)

Anti-Dopamine 1: 1000 (normal range: 500-2000)

Anti-Dopamine 2: 2000 (normal range: 2000-16000) VERY LOW

 

 

The letter from the study says "We measure the levels of antibodies against the neural antigens lysoganglioside, tubulin and dopamine receptors D1 and D2." "Antibodies may induce increased signaling of neuronal cells and cause release of too much dopamine in the brain."

 

So the DS13 with high D2 (at the time) had no tics and the DS10 with low D2 had tics. Dr. B said that the results were what he would expect. So I wait in hopes that this very wonderful gem of a doctor will be ble to get Dr. Cunningham to clarify and then find that we may be able to try Amantadine after all and it will be the help that we need!

 

I hope this helps!

Linda

 

I am wondering - did they put hte VERY LOW and VERY HIGH on the report? Those look like low end of normal and high end of normal ranges to me. I don't have my DS's ranges in front of me, but i know that one's he was high in ... he was over the upper limit.

 

Also - as per the explanation I just wrote for LLMs question regarding the areas of the brain - it would make sense that your DS 13 had OCD and movement disorders as D2 receptors are found in high concentrations in the basal ganglia, which controls movement, while your DS11 had symptoms more closely associated with limbic system and cortex issues (D1 receptor). Your DS 10 is harder to relate to the ranges ... and I don't really have an explanation for that right now.

 

again - I think this is all more hypothesis than fact at this time... I've not seen a paper or presentation about this. Perhaps others have?

[kimballot]

Powerofprayer, you are right. Dopamine is said to contribute to TS tics.

 

I personally think that in some cases of tics you have to look at the Camkinase II level as well. At some point I have either read or some doc has said that high CamK kids are usually ticcer kids. I suspect when someone figures out what mechanism is going on with that high CamK, they will figure out what is causing some cases of tics.

 

Yes -I absolutely agree. Cam Kinase is a precurser to dopamine. That is, one of the many functions of Cam Kinase is to produce dopamine.... so really, it may be just one more way that dopamine levels are being changed in our kid's systems - presumably by increasing dopamine. The idea behind Cunningham's work, I believe, is that the antibodies from our kids blood react with neuronal cells to produce cam kinase at higher levels than kids without PANDAS.... our kids' antibodies actually produce more Cam Kinase than kids with ADHD, OCD, or tics who do not have PANDAS symptoms (sudden onset associated with an infection). BUT our kids' antibodies produce less cam kinase than kids with sydenham's chorea.

Edited February 22, 2013 by kimballot

[JAG10]

It's interesting how so many of these conversations involve the "too high or too low" debate where we pseudo scientists try and figure out what's going on and we end up in a state of confusion.......is dopamine too high or too low? Is the problem histamine is too high or too low? Is it ASO or anti-DNAse B antibodies are too high or completely absent?

And then there's the fact that its never that simple anyway. Different types of dopamine affecting different areas of the brain.......if you try and use meds to regulate the dysregulated areas, will you upset the apple cart in other areas? I guess all that's left is trial and error.

My personal guess is that a child can have some "baseline dopamine dysregulation" that is made more unstable and magnified beyond recognition with infections. Some kids may not have any baseline dysregulation- those would be the completely normal to nuts kids and some may have a considerable amount.

Edited February 22, 2013 by JAG10

[LNN]

JAG - that's kinda where I end up too. It's not all "Pandas" and when infection is gone, everything is honkey dorey. Latimer told us years ago not to do a neuropsych eval during a flare because we'd be measuring the impact of the disease. Wait until things were settled and then measure if anything remained. We did just that and while there's still a considerable swing/decline during a flare, there is some baseline stuff that we're needing to deal with. Some may be due to harm done by some many years of chronic infection, some may be due to the way DS's brain built accommodations to bypass circuits that weren't working, and I think some stuff was there in toddlerhood before the s*** hit the fan.

 

I guess that's what makes me so interested in the epigenetics stuff. It may hold answers for baseline things we can "fix".

 

Further complicating the story is that some genes, like COMT, effect the rate at which dopamine is dissipated/used. This NY Times article talks about how your rate of "metabolism" if you will, greatly effects executive functions and decision making. http://www.nytimes.com/2013/02/10/magazine/why-can-some-kids-handle-pressure-while-others-fall-apart.html?pagewanted=1&_r=5&hp&

 

Still, helpful discussion.

 

BTW - PowerofPrayer - there are additional triggers for tics beyond dopamine. Glutathione levels and your ability to rid your body of toxins can also cause tics. Things like a herxheimer response to a bacterial or fungal die off can trigger tics. Your HLA genes play a role as well. None of it is simple.

[kimballot]

.if you try and use meds to regulate the dysregulated areas, will you upset the apple cart in other areas? I guess all that's left is trial and error.

My personal guess is that a child can have some "baseline dopamine dysregulation" that is made more unstable and magnified beyond recognition with infections. Some kids may not have any baseline dysregulation- those would be the completely normal to nuts kids and some may have a considerable amount.

 

Yes - you can "upset the applecart" in different areas. For example, one theory of schizophrenia that is due to too much dopamine in the limbic system... so they give the individual meds to block dopamine, which does reduce hallucinations. The meds are better now, but the older dopamine blockers often produced some parkinson symptoms early on due to decreasing dopamine in the basal ganglia. Additionally the brain has plasticity and changes over time. The number of receptors actually change over time. So, people with schizophrenia who are on dopamine blockers for a long period of time actually can develop MORE dopamine receptors to try to accommodate for this. As they develop more dopamine receptors in the basal ganglia, they can start having unusual muscle movements called tardive dyskinesia. I believe this is seen less often now than in the past as I think newer drugs are better and controlling for this. However, that is why we need to be carful with meds that mess with these levels. It is not as simple as it looks on the surface.