The GTS gene isn’t the only gene involved with Tourette syndrome. Tourette’s is actually caused by many genes (no one knows how many yet) that are slightly abnormal. The GTS gene seems to act as a catalyst for all the other genes, and makes their effects more pronounced. Each of these minor genes codes for a trait too, and the abnormalities in the genes cause an abnormality in its product.
Every thought that you have and action that you perform, begins in the brain . Billions of brain cells, called neurons, connect to each other to form pathways. When a thought is had, an electrical pulse starts at one neuron and passes from one to another down a long predetermined pathway. (To be honest, no one has worked out how this actually translates into conscious thought...but we’ll leave that to psychologists and philosophers to fight out.) However, neurons aren’t actually connected directly to each other. Between the end of the dendrites (the little “tentacles” coming out of the cell body) and the body of the next cell there is a gap of about 10-20 nm. (1 nm is one billionth of a metre). This gap is called a synapse. The electrical impulse cannot cross the synapse, so chemical transmitters are used – neurotransmitters. When the electrical impulse arrives at the end of the dendrite, a chemical neurotransmitter is released which crosses the gap and sparks off another electrical impulse on the other side. This is how messages get around the brain.
Dopamine
In Tourette syndrome, however, there appears to be a problem with the receptors of some of these neurotransmitters.
It had been thought for ages that many of the tics in Tourette’s are caused by too much of the neurotransmitter Dopamine.
Comment: this would have made TS the exact symetrical opposite of PD, offering a "natural" solution for each other in their respective "deffects". However, if it is not an excessive/deffective dopamine production at play, but an excessive number of dopamine receptors vs a diminished dopamine production, such mutual "solution for deffect" exchange (a biochem version of the old saying: "one man's trash is another man's treasure" is ruled out. But, is it? Some researchers have doubts about the "progressive death" of dopaminergic neurons as the underlying cause of PD. Could it not be that PD is actually a reduction in dopamine receptors, rather than or plus a reduction in dopamine production, making it the exact or partial opposite of TS? This would explain the vastly superior relief of symptoms of L-dopa (more arrows-dopamine- hitting all available targets -dopamine receptors- to follow thelma's analogy.instead of imperfect arrows -dopamine agonists- trying to hit some of the already reduced target population. What would be the implications of this? Or else, even if the TS's excess dopamine receptors proposal and the PD's lack of dopamine one prove correct, could one not inspire a solution to the other and/or viceversa? Fuel for thought.
The theory says:
The brain tends to randomly fire off weak impulses of electricity just to check that everything is connected and healthy. These pulses are so weak that the thought or action they code for does not actually occur. In Tourette’s, however, when some of these random pulses reach the synapses, a larger than normal amount of dopamine is released. And the more dopamine, the stronger the signal released when the chemical reaches the other side. And this stronger pulse would be amplified again at the next synapse, and so on. Very soon, the action would actually be performed.
However, this theory was not quite right. Post-mortem studies of adults who were diagnosed with Tourette syndrome, showed a large increase in dopamine receptor sites. [COLOR="Red"][B]Dr Comings (1991) then discovered that defects in the genes D2A1 and DAT2 increases the number of Dopamine Type Two receptors (D2) while another gene (unidentified) affects the D3 receptors. The increase was about 44% more on average across the whole brain. This would have the same effect as excess dopamine on multiplying the signals passed through the brain, but would do it in a different way.
When the neurotransmitters are released into the synapse, a lot is wasted. At the far end of the synapse there are uptake carrier sites. These sites grab onto the neurotransmitter and, once the chemical is bound to the site, it releases the impulse. But not all of the neurotransmitter reaches the uptake sites. It’s like shooting arrows at a target while blindfolded – only some of them are going to hit it.
If you increase the number of targets though, you’re more likely to hit one. It’s the same with dopamine uptake sites, if you have more sites; more dopamine is going to be absorbed. And more dopamine means a stronger impulse at the other end.
Many medications for Tourette’s are dopamine blockers. Once in the body they get into the synapses and bind with the dopamine uptake sites. The dopamine blockers don’t trigger an impulse, they just sit there and stop dopamine from using the uptake sites. This effectively reduces the number of uptake sites in the synapse.
The reason you get sluggish when on dopamine blockers is that ALL movements require the passage of dopamine, not just tics. The blockers do not discriminate between the purpose behind movements .
[B]
Comment: The same exactly happens with psychotics/schizophrenics treated with early antipsychotics, for example Haldol (haloperidol). In their case, based on the assumption that they have too much dopaminergic/dopaminomimetic action in some "thinking" and "feeling" related sites in the brain, causing "psychotic" thoughts, the strategy seeks to block the dopamine receptors at these sites. Problem is, Haldol also goes to work on any other dopaminergic receptor sites, including those that control movement, so, after a while on Haldol, a psychotic person improves his/her psychosis but ends up with Parkinson's like symptoms instead. What a trade-off, a situation which is, fortunately, mostly reversible if the offending drug is withdrawn. Haldol is one drug used in Tourette's. The same mechanism applies to PD, where the dopaminergic/dopaminomimetic strategies followed to obtain symptomatic relief, (chiefly by L-Dopa/dopamine agonists) when excessive (i.e.: overdosing) cause excessive Dopamine activation throughout the brain (which does not discriminate), not only in the movement centers, with the resulting "dyskinesias" but also in "thinking" and " feeling" sites in the brain, causing "psychotic" thoughts, including mental restlessness, visions, and various OCDs, such as, uncontrollable gambling/shopping, sexexcesses, etc., which require in turn yet another drug to control them. In earlier times, this resulted in a "no win" situation, as "early" antipsychotics (such as Haldol) went to work precisely on blocking dopamine receptors, indiscriminately, resulting in less psycosis-intended target- but more PD-unintended target, i.e.:the perfect "viscious circle". This has been resolved quite well (as far as symptomatic relief goes) by using so called "atypical" or "latest generation neuroleptics" (i.e.: antipsychotic drugs), such as Seroquel, which have a lower antidopamine action. Lots of parallels folks. Fuel for thought.
[COLOR="Red"]
Norepinephrine
Dopamine is also converted in the body to norepinephrine.
Brain norepinephrine plays a role in general arousal level. Norepinephrine is at lowest levels while asleep, and is released in large quantities to wake you up in the morning.
Comment: This offers a straight and elegant explanation to the puzzling paradox of why PD symptoms dissapear while we are asleep but return with such ferocity and suddenness as soon as we wake up. Because, while asleep, both dopamine and norepinephrine requirements are at their minimum (thence a slow release levodopa/carbidopa tablet, such as Sinemet CR, can carry us thru six or seven hours of sleep, provided some other PD related (e.g.:urinary urgency) or unrelated symptom (e.g.: a barking dog or passing thunderous gas), wake us up sooner. But, as soon as waking up, whatever little dopamine is left in the brain, is used up, pot-bottom scrapping, we could say, by the need to make norepinephrine. This explains too, why does it take quite a bit more and progressively more L-dopa and time, to "prime" the wholy dopamine-starved system each morning, many times resulting in a painfull "off", which is resolved once circulating levodopa reaches a minimun-therapeutic- level in the body/ brain and enough dopamine gets made to satisfy both the "movement control", psychiatric and norepinephrine needs and other needs, bodywide (e.g.:heartbeat regulation, mielin, eyes'retina cells, etc.)
In addition, all parkies (as Touretters) know all too well how any sudden stress appears to counteract the action of antiparkinsonian drugs so dramatically. What happens in such a case, is not that levodopa stopped making dopamine, but rather that all the resulting dopamine is monopolized to make epinephrine and norepinephrine, involved in the "fight-flight" automatic response, supposedly, a remnant from earlier, primitive stages in man's evolution, rendered redundant (really?) by our more evolved, civilized, current stage [/I] Hormonal norepinephrine is released from the adrenal glands (located just above the kidneys) during stress. It is part of the “fight-flight” response to danger and increases heart rate and blood pressure, relaxes smooth muscle to allow more efficient breathing and increases the conversion of food and sugar into energy. This may cause part of the excess energy Touretters have, as well as things like difficulty sleeping and increased appetite.
Comment: It appears that the"fight-flight" response includes another very distinct component, as in: "fight-flight-freeze" (I've witnessed a case, first hand, where all three reactions to sudden and present danger were exhibited, with an overall successful outcome (for the intended victim): a hare, startled by a tracking small dog. The hare first faced her attacker, tooth and nail, enough to balance out the surprise factor favoring the dog, then run away, then "froze" (lying down on the ground, very low and very still -the quintessence of "keeping a low profile"- once on tall grass), after a quick, sharp and sudden change of direction caused the dog to overshoot the target loosing visual contact with her, moment she chosed to dissapear altogether by laying low and motion-less, forcing the dog to switch over to his nose for guidance to get back on her track, but this required random and time consuming "tacking" type back and forth, side to side movements which the hare used conveniently to make a stealth and swift escape in a different direction. By the time the dog picked up her scent again, she had put a safe distance between her and the doggedly pursuer or someone might say "doggone dog". It is been suggested that the Parkinsonian type, due to personality and/or heredity (are they really independent or interdependent entities, or better, isn't such distinction "artificial" and borne out of from our human tendency to separate things which are really different manifestations of the same substrate? is fixated in the "freeze" response to stress, which by itself may be the unhealthiest (yet more "civilized" and socially promoted) but totally lacking the capacity for tension relief, whereas "fighting" and/or "flying" AND (but not OR) "freezing" or better yet a "healthy" combination of the three (as in the hare example above), by their sheer ENERGY expense (in fact a rather explosive burst thereof) offers the best mechanism to "vent" the pressure created by stress , resolving as nature intended it, what in "civilized"man turns a conflict intended for outward resolution into an inward, self-destructive, self-perpetuating, internalized, unresolved biochemical conflict with outward motor, psychiatric, digestive and other disturbances. More fuel for thought.
Hormonal norepinephrine is also important for learning and the formation of memory.
Comment: and so is Acetilcholine (active on memory formation,) the other main player in the currently accepted theory of PD, making it another double-faced target for symptomatic PD relief, anticholinergics being the mainstay of the chemical arsenal against PD, before and even alongside with the adoption of L-Dopa, the "gold standard" drug for symptomatic PD relief.
Because norepinephrine and dopamine are part of the same chemical pathway, the body has to make a choice between which of the two chemicals it needs. The body is very clever and has its own ideas about how much of each chemical it needs, focusing primarily on the balance in the most vital area, the brain. When a Touretter is in an unmedicated state the body detects that it needs to produce a lot less dopamine because the messages are getting through very easily. So the dopamine is converted to norepinephrine in an attempt to lower dopamine levels to the body's idea of normal (actually lower levels than in non-Touretters). So unmedicated Touretters have higher than average norepinephrine levels.
When a Touretter is on a dopamine blocker medication, however, the body feels that messages that should be getting through are not.
This is a weird thought to grasp but for Touretters (and everybody else, you bet) tics are the desirable normal state for the body, and it will fight to keep them.
So the body will stop producing as much norepinephrine in order to increase dopamine levels and help the messages get through more easily.
The problem with this is not only are you getting sedation from the lack of dopamine getting through (because producing more dopamine won't get it past the blockers, just like having more people on one side of a wall won't get them through it) you get sedated by the sudden drop in brain norepinephrine.
Some people feel their memory gets weaker if they are on large doses of anti-psychotics and this would be why. Lower norepinephrine levels mean that the body has a bit more trouble forming new memories.
Comment: Now, this "self adjusting" mechanism of the body human's chemistry is soooo important to be understood, because it explains chemical addictons as well as chemical dependency (including our own dopaminergic/dopaminemimetic and/or anticholinergic/choline receptor blocking dependency) or any chemical intervention which is counteracted energetically by the body's/brain's own set orders (be the "stay healthy order" or "stay diseased order", respectively, as dictated by, for example, genes in proper working order or deffective ones. This UNDERSTANDING of what might be said that both "HEALTH" AND "DISEASE" WANT TO LIVE ON FOREVER, JUST AS MUCH AS ANY AND THE NEXT LIVING ENTITY AND THEIR BROTHER, thanks to their built-in mechanisms, which may include, besides genetics, some other mechano-chemical "viscious circle" mechanisms, SHOULD redirect our attention to the correct "curative" approaches to disease resolution (which are bound to be counterintuitive, as explained above) vs the current "maintenance" or "managing" of disease symptoms approach. For an understanding of the latter, I strongly recommend everybody to read the very entertaining account of the history of the chemical approach in the management of PD through the ages, FOUND at:
http://neurotalk.psychcentral.com/sh...16&postcount=1
Serotonin (5HT)
Serotonin, often known as 5HT (but actually not), is another type of neurotransmitter. It affects many of our positive and negative experiences of life, so it is often known as the “happy drug”. Very generally, high levels of serotonin bring on good moods - low levels bring on low moods. For this reason antidepressant drugs work to delay the breakdown of serotonin and thus lift our mood.
Serotonin is produced in the body from Tryptophan, a chemical found naturally in high carbohydrate foods. As can be seen in the diagram to the left, about 10% of the body's tryptophan intake is converted to serotonin via the stage of 5HT (5-hydroxytryptophan). The other 90% is converted to kynurenine.
Serotonin acts on three different receptors numbered 5HT1, 5HT2 and 5HT3.
When serotonin acts on a 5HT1 receptor it mainly causes disruption of neurochemicals. This is the receptor pathway that ensures you are not flooded with serotonin, the 5HT1 receptors stop production of any more serotonin, both in the body and in the brain. It also causes the levels of noradrenaline released into the body to drop.
When a 5HT2 receptor comes into contact with serotonin it causes a stress management reaction. The human body can be stressed in many ways; injury, hard work, fear. The reaction of 5HT2 is to cause inflammation of any injured area (e.g. bruising), create faster breathing, send more energy to muscles, contract the smooth muscle in the body (i.e. the stomach to slow down digestion) and basically speed up the metabolism.
5HT3 receptors are the ones that make this the "happy" drug. Serotonin is converted in the brain through a neurochemical pathway into a feeling of well being. (Don't ask me how this works...no-one knows yet.)
What this means in Tourette syndrome is quite convoluted. It has been shown by many researchers that the levels of serotonin in Touretters is quite low. This is immediately made obvious by the fact that anti-depressants can help control tics.
Dr Comings(1990,1991) went further to find that there is a problem in the Tryptophan to 5HT to serotonin pathway in Touretters. Instead of turning 10% of our dietary tryptophan into serotonin we only use 0 - 4%. This means our serotonin production is very low and our kynurenine levels are high.
Oh crud!
"our kynurenine levels are high"
In 2001 I couldn't find out what this implied.
By 2004 I still had no idea.
Now I know.
It's not nice.
I always guessed kynurenine was somewhat toxic...after all, it does have the word "urine" in it and that's one of the body's most toxic wastes. But recent research seems to show that where you find high levels of kynurenine, you find brain damage. Most of the research has been done on HIV patients (HIV causes the higher levels of kynurenine), but there have also been studies that show kynurenine inhibitors (things that stop more of it being made) can reduce the risk of Alzheimer's disease, inflammatory brain conditions, and dementia.
Wow. Aren't you glad I found that out!
So what does this cause physically?
If a low amount of serotonin hits the 5HT1 receptors then norepinephrine is released in larger quantities, making the whole norepinephrine/dopamine problem worse than it already is. This is probably the main reason why SSRI's work on tics, because they would reduce the amount of norepinephrine in the body.
If a low amount of serotonin hits the 5HT2 receptors the body is less able to cope with stress. You are more likely to react badly to temperature changes, low food levels, and injury.
If a low amount of serotonin hits the 5HT3 receptors, you get depressed. This tends to also make you eat more in an attempt to raise serotonin levels.
All this means that it is important to have decent serotonin levels in the body and the brain. This is easy for the body, you can just take a serotonin tablet. But the brain is protected by the BBB (blood brain barrier) which screens out most chemicals from the blood, including serotonin. The way we deal with this is to use SSRI's. Selective Serotonin Re-uptake Inhibitors stop the serotonin in the brain from being broken down, so there ends up being more around.
However, SSRI's won't work forever.
As has been said before, the body has a preset idea of what is a "normal" amount of neurochemical to have. With serotonin in Touretters, that level is quite low. But if you put more serotonin into the system via SSRI's, then the brain will make even less natural serotonin. The artificially higher levels will also begin to "burn out" the serotonin receptors, so more is needed to get the same result. This is the reason why SSRI levels have to be upped occasionally as the drug just stops working. It also explains the huge withdrawal after stopping SSRI's, the body is not producing serotonin, but you need high levels to get any reaction...in Touretters this translates to depression and lots of tics.
To understand a bit how this "burn out" works:
"Imagine a pool. It starts off full of salt water. By the side of the pool sits a life guard, his job is to make sure that (a) the pool is full and (b) that there isn’t too much salt in the pool. However this particular pool has a slow leak from the bottom. To counter this ten men are hired to walk to a nearby sea, fill a bucket with sea water, and walk back to pour the water into the pool.
In a normal pool, the men fill their buckets from the Mediterranean sea, which has exactly the right level of salt for the pool. The pool stays full, and the salt level stays correct.
In a Tourette pool, however, the men fill their buckets from the dead sea. The dead sea has 4 times the salt of the Mediterranean, so as time goes on, the salt levels in the pool rise. The life guard notices that the pool is getting too salty, so as the next man comes to tip in his bucketful, the life guard talks to him, and he puts down his bucket and heads to the bar. When the second guy comes and tips in his bucket, the lifeguard also talks to him, and one by one the men put down their buckets and go to the pool bar.
Because the pool is leaking, the salt levels in it begin to drop, but so does the water level. It actually starts to drop quite suddenly after the last bucket is put in, and soon the water level has gone from full to too shallow to swim. The life guard runs over to the bar, grabs the men and they run back to the pool, pick up their buckets, and begin running to the sea to fill them up. The water level in the pool begins to rise at a moderate speed, but soon the men are drunk from the bar and are tired from all the running. So the life guard hires another 5 men to help bring in the water. So now there are 15 men lugging water from the sea to the pool. The pool level rises a bit, until the lifeguard notices that the pool is getting to salty…"
So although SSRI's are very effective, they should be considered carefully before any are taken.
Dr Comings (1990, 1991) believed that the serotonin gene at 4q31 was the GTS gene, but that has been disproved.
The best way to raise serotonin levels is exercise. Not only are levels raised during the activity, they stay high for a couple of days afterwards.
Androgens
It has long been known that androgens (such as testosterone, the male sex hormone) affect Tourette syndrome. This is why Tourette syndrome affects three times more males than females. Also, Shapiro et al. (1988) and Scahill (1990) reported that anabolic steroids made Tourette syndrome symptoms worse.
The reason these androgens aggravate Tourette syndrome is probably related to serotonin. It is known that steroids lower serotonin levels, and it is probable that high levels of other androgens will as well.
Cortisol and DHEA
Cortisol is known as the “stress hormone”. It maintains blood pressure and cardiovascular function, reduces the immune system’s inflammatory response, balances the effect of insulin in breaking down sugar for energy, and regulates the metabolism of proteins, carbohydrates and fats. When the body is stressed, the level of cortisol in the body increases. (e.g. athletes, pregnant women, depressed people, alcoholics, malnourished people and those with panic disorders have higher than normal levels of cortisol.)
It is believed by many that cortisol has a negative effect on Tourette syndrome; that is, it makes tics worse. So it may be cortisol that makes tics worse under stress.
Discoveries (Biol. Psychiatry 1996 – as cited by J. M. Howard 1997) have shown that Touretters have significantly higher levels of corticotropin-releasing factor, the precursor to cortisol, than normal.
Dehydroepiandrosterone (DHEA) is an “anti-cortisol” hormone according to Howard. DHEA has been known to have calming effects and is packaged by some companies as a “wonder anti-aging drug!” It is believed that low levels of DHEA will add to the negative effect of high cortisol levels.
The strange behaviour of antipsychotics and neuroleptics when used to treat Tourette syndrome can be partially explained by DHEA/cortisol reactions. It is believed that these drugs cause the release of prolactin, the precursor to DHEA. This increased DHEA counters the high cortisol levels. The drugs, unfortunately, overwhelm the natural production of DHEA and “burn out” the adrenal glands. This then means the levels of cortisol rise again, usually to a higher level than where they started.
This means the brain is not getting enough DHEA. Howard suggests that tics are actually small seizures designed to stimulate DHEA production. How this works:
"...the increased melatonin found in untreated epileptics builds up and is released so that nerves are shut down. Individuals susceptible to epilepsy must have entire sections of the brain shut down so much that they "rebound" and call up a large response of DHEA. It is this rebound response that is the large area of stimulated nerves that cause the seizures. Once the brain has stimulated sufficient DHEA, then the seizure stops."
So TSers may find that (directly affected by DHEA levels) this rebound in small sections of the brain (instead of large sections as in epilepsy) causes not an overall muscle contraction seisure; they cause a small nerve impulse to be sent; which gets multiplied by the Dopamine receptor abnormalities described above. So the brain's attempt to create DHEA, in order to relieve stress, may cause tics that way.
This (in my mind) is actually the most plausible explanation for how tics start.
Stress ? need for more DHEA ? mini seisure ? small electrical impulse + excess dopamine receptors
= TICS
DHEA levels are known to start low in childhood and e during adolescence to peak at about age 25. It is also common knowledge that Tourette syndrome often decreases in severity or disappears following the same pattern. DHEA then may be the reason for this decrease.
Also, in an article on epilepsy, Howard states:
"I suggest migraines result from low MLT and increased DHEA. Women produce more DHEA from birth than men. This extra DHEA should have most effect on migraines prior to the onset of interfering sex hormones, before puberty. It has been found that "when the onset [of migraines] is below the age of puberty there is a striking predominance of women over men in a ratio of 3:1," (Headache 1994; 34: S8). It is part of my theory that the hormone, testosterone, causes DHEA to be used for "testosterone target tissues." This use of DHEA by these tissues should reduce the availability of DHEA, i.e., increased testosterone should decrease migraines. "
This is of interest to us as the ratio of Women over Men in Tourette syndrome is the exact opposite; 1:3. If testosterone does cause DHEA to be used for "testosterone target tissues" (parts of the body that make men men) and reduces overall DHEA then not only will women have 3 times more DHEA to aggravate migraines, they will have 3 times more DHEA to stop tics!
References
David E. Comings (1990) Tourette Syndrome and Human Behaviour
David E. Comings (1991) Search for the Tourette Syndrome and Human Behaviour Genes
buy Dr Comings' books at amazon.com
James Michael Howard (1997) A potential explanation of Tourette's syndrome and DHEA, Migraine and Epilepsy
Norepinephrine info site
http://www.csuchio.edu/psy/BioPsych/norepinephrine.html
Getting 'high' on serotonin - Neurotransmitters and Health website
Ron can this be of information on dopamine receptors,
hard to find information that sticks to the subject and doesn't go into the symptoms of parinsons and what it entails. Will keep trying for more up to date info for you. but the information contained here on Migraines and Tostesterone is now accepted as fact so that speaks well for the author
06-27-2007, 08:17 PM
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I've been glued to e-book on history of PD
Interesting to note that chemical therapies of PD...
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