Serotonin

   The serotonin system implicated as a factor in some cases of autism since the finding in 1961 of elevated serotonin levels in the blood of patients with autism, yet the mechanism for this has "not yet been determined" (Cook, 1996).

   Considering the well-established fact that thyroid hormones control serotonin transport, receptors, etc.,  - - -  how has it been possible that no one has ever investigated serotonin levels and compared properly to actual thyroid hormone levels in autistic children? 

   After all, there are hundreds of papers on MEDLINE on serotonin and thyroid hormone inter-action. [T3 (135); TSH (249);TRH (490), etc., etc.]

   A finding of serotonin dysfunction in autism should have been a clue to look in-depth at thyroid dysfunction a long time ago, as simply ALL serotonin activity is controlled by thyroid hormones.

POINT: Simply ALL central and peripheral serotonin neurotransmission is affected by low free T3 and high TSH levels.

REMEMBER: feedback mechanism -> TSH will cause Low Free T3 -> Low Free T3 will cause even higher TSH.

   T3 regulates serotonin transport and uptake (Sjoberg et al, 1998;Schwark, 1978; Rastogi et al, 1978, 1979); receptor expression, density, and binding (Kulikov et al, 1999, 2000; Cleare, 1996; Richards et al, 1990); pre-cursor activity (Beltowski et al, 1992; Rastogi et al, 1978, 1979), etc..

   These activities change depending on age, and are identical to the age-related differences observed in the autism literature. (i.e. Croonenberghs, 2000; McBride et al, 1998; Herault et al,1996;Takahashi et al, 1976; Martineau et al,1987).

1) 5-HT2A RECEPTORS

   Hyperserotonemia in autism has been associated with increased 5-HT uptake in one subgroup, and  decreased 5-HT(2A) binding in another (Cook et al, 1993, 1996).

   Both of these factors are regulated by TSH and Free T3 (Schwark, 1978; Kulikov et al, 1999, 2000; Cleare, 1996; Rastogi et al, 1978, 1979; etc).

   Increased 5-HT uptake is caused by elevated TSH levels,  5-HT(2A) activity is regulated by Free T3.

As one example, McBride et al. (1989)  showed reduced 5-HT(2A) receptors in autistic children.

   In hypothyrodism, it is believed that the decrease in cortical 5-HT(2A) receptors observed in low T3 conditions is the main neurochemical event underlying the impairing effect of hypothyroidism on 5-HT neurotransmission in mature rat brain (Kulikov et al, 1999; Cleare, 1996), and that these conditions are the result of insults in the most-crucial period -> the neo-natal period [-> pertaining to the first four weeks after birth], and especially the first few days after birth. (Evans et al, 1999; Rastogi, 1978, 1979; Richards et al, 1990)

   At this period T3 is totally ESSENTIAL for the optimal development of 5-HT metabolizing systems in maturing brain, having the power to affect serotonin metabolism for life (Evans et al, 1999; Rastogi, 1978, 1979).

ONLY free T3 can cause alterations in 5 -HT(2A) levels in brain regions (i.e. Kulikov et al, 2000, 1999)

   The serotonin (5-HT) 2A receptor is now targetted for future pharmacotherapy considerations in treating autism (Okado et al, 1999) as it has also intimate relations with glutamate (Carlsson et al, 1998),  abnormal levels of which are usually observed in autism as well (Moreno-Fuenmayor et al, 1996; Rolf et al, 1993).

   5-HT(2) receptors are bound to Gq/11 (i.e. Alberts et al, 1999). Serotonin activity in platelets is mediated via the 5-HT(2) receptor complex.

    Regarding serotonin and melatonin it should be noted that studies have shown changes in 5-HT2A, muscarinic M1 and GABA(A) receptors in tissue from subjects with schizophrenia. Animal studies suggest a site in the cortex where there would be an interaction between serotonergic and cholinergic innervation and that this interaction would involve the 5-HT2A and the M1 receptor. This site, in turn, would be a potent modulator of GABA activity and, hence, levels of GABA(A) receptors (Dean, 2001).

   ALL are mediated by T3, TSH and Gq/11! It is the ONLY common factor in all these implications!

2) TRYPTOPHAN

Tryptophan is the precursor of serotonin (5-HT).

   Elevated FREE plasma tryptophan levels in autistic subjects have been observed (Bursztejn et al, 1988;Hoshino et al, 1984),  while TOTAL tryptophan levels did not differ (Hoshino et al, 1984).

    Hoshino et al (1984)  found free tryptophan was positively associated with CPRS-1 or WWPAS score and negatively correlated with the development quotient (DQ).

[positive->both factors increase; negative -> one variable increases when the other decreases]

    While blood plasma tryptophan is incrased, brain tryptophan is decreased in autistic children (Cook 1996).

    Exact same conditions can be seen in Low Free T3, again - it's important to realize that such conditions are ONLY seen with low FreeT3.

    When rats are made hypothyroid, tryptophan levels in blood plasma increase (Beltowski et al, 1992),  while in brain they decrease (Rastogi 1978) - identical to the findings in ASD.

    T3 administration corrected the levels to normal, but only when it was done at the period of greatest risk. At 60 days (- > puberty in rats is at  50 - to 60 days) T3 supplementation had no effect on serotonin metabolism.

   Puberty-related changes in serotonin levels of autistic children have been observed by many (i.e Croonenberghs et al, 2000). The reason why levels change after puberty is because in the mature brain, the presynaptic entities of 5-HT neurotransmission are resistant to large variations in T3 levels. (Kulikov et al, 1999)

   It must be mentioned here, that if only autism"experts" could be convinced to look at thyroid regulation of serotonin, they would see that such specific defects as seen in autism can ONLY be due to interference at certain time periods. Comparisons of the symptoms observed in the autistic sub-groups with the literature on thyroid status would allow for direct conclusions to be drawn as to WHEN the damage has likely occured.

   Thyroid status regulates the blood-brain barrier (BBB) transport of tryptophan and other neutral amino acids. Low Free T3 decreases the disposition of biogenic amines in the CSF, which is a hall-mark of autism (i.e. Okado, 1999; Partridge, 1979).

   This thyroid-hormone-regulated transport system is also induced in states of liver encephalopathy and this process is thought to be the primary cause of the increased brain tryptophan and serotonin levels in cirrhosis (Partridge, 1979).

   Co-incidentally, 100 percent of children investigated  in one study on autistic children showed liver dysfunction (Edelson, 1998).

3) TRYPTOPHAN/LNAA RATIO

   The serum tryptophan to large neutral amino acids ratio (Try/LNAA) is considered a reliable marker of tryptophan availability for brain serotonin synthesis. (D'Eufemia et al, 1995) 

   D'Eufemia et al (1995) found reduced tryptophan/LNAA ratio in autistic children (35%) when compared to the normal controls.

   Reduced  (Try/LNAA) has also been associated with low free T3 (i.e. van der Mast et al, 2000; Schreiber et al, 1991).

   It has also been associated with an increased ratio of inactive reverse T3 (rT3) to active (FreeT3) (van der Mast et al, 2000), which obviously results in lower available free T3. This ratio disturbance may also be caused by fluoride, as was clearly shown by Lin Fa-Fu et al (1991) in areas with even less fluoride in the water than is used for  public "optimal" water fluoridation measures (Lin Fa-Fu et al, 1991). Other fluoride compounds will also cause increase of rT3, such as trifluoromethane products (i.e. Dodd et al, 1999) 

   At water fluoridated at 1 ppm, rats have shown impaired thyroid hormone transport and low Free T3 levels (Bobek, 1976).

   Keep in mind that  water fluoride levels at 10ppm are required in rat studies to cause similar enamel disturbances as seen in man... (i.e. "dental fluorosis", or dental hypoplasia)

   That is because a rat's basic metabolic rate (BMR), controlled by Free T3, is much higher in rats than  in humans, therefore a much higher fluoride dose (speak TSH) is required to produce similar plasma levels as in humans.

   A disturbed rT3/T3 ratio is a sure sign that peripheral T4 to T3 synthesis is disturbed, as the thyroid itself only releases minimal amounts of rT3.

   For T3 the optimal pH is 6 and for rT3, 9.5. The converting activity for both T3 and rT3 is temperature dependent and can be suppressed by heat, H2O2, merthiolate, PTU (Hoffken et al, 1978) as well as by fluoride. rT3 and to a lesser degree iodide, are able to inhibit the production of T3 in a dose-related fashion. Therefore the pH dependency, rT3 and iodide may regulate the availability of T3 or rT3 depending on the metabolic requirements of thyroid hormones. (Hoffken et al, 1978)

PLATELETS

Increased density of the platelet serotonin transporter in autism has been reported (Marazziti  et al, 2000).

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