Human
emotions and behaviours are influenced by parallel signals from the nervous
system (i.e. the brain) and the endocrine system. The two systems are interconnected and so
your state of mind in controlled by hormones that you cannot directly control
and the nervous system which you can learn to control. For example, you can make yourself happy,
unhappy, or depressed with the power of your mind. You can train yourself to overcome fear. Some people are clearly very much better at
doing this than others; but the potential to do so lies within all of us,
autistic or neurotypical. This also
explains why singing makes you happy and rapidly reduces cortisol, your stress
hormone, as we learnt in an earlier post.
So on the
one hand we need to understand any in-built hormonal disturbances in autism and
then see how to best tackle them using the hormonal system and the nervous
system. This may sound like fantasy but
the more you learn about it, the more plausible it becomes.
Serotonin
Most people
have heard of Serotonin; it is frequently thought of as the “happy hormone”.
As we have
learnt in this blog, the human body is not like any man-made invention, it
seems to function in quite irrational ways.
Serotonin is found mainly in the intestines and less than 10% is in the
brain (and CNS), but it is not the same serotonin. Serotonin cannot cross the blood brain
barrier. In autism serotonin in the
blood (produced in the intestines) tends to be elevated, but the level of
serotonin in the brain appears to be reduced.
So there appears to be a failure in the entire serotonin system, the one
for the brain and the one for the blood.
Drugs that
lower brain serotonin are often used to treat the symptoms of autism. Even Temple Grandin admits (on her own website) to
being on a low dose of Prozac to control her anxiety. In spite of a long list of side effects, many
children with ASD living in the US are prescribed this serotonin lowering
drug. Prozac is a heavily prescribed
antidepressant drug and is a selective serotonin reuptake inhibitor (SSRI).
Somewhat
bizarrely, Prozac is linked to an increase in suicidal tendencies. As is often the case, many drugs have
secondary or tertiary modes of action; you will experience all of them.
In the
language of your doctor, low brain serotonin would be called central
serotonergic hypoactivity, but don’t go asking him to test it, because he
cannot. All he can do is measure the
level of serotonin in the blood or urine, and probably tell you that it is slightly
elevated and not to worry.
Researchers
have known about this serotonin paradox in autism for many years. To my surprise a researcher at Yale
University even made a mathematical model to better understand it.
Since the early 1960s, the most consistent pathophysiological
finding in autistic individuals has been their statistically elevated blood
5-hydroxytryptamine (5-HT, serotonin) levels. However, many autistic
individuals have normal blood 5-HT levels, so this finding has been difficult
to interpret. The serotonin transporter (SERT) controls 5-HT uptake by blood
platelets and has been implicated in autism, but recent studies have found no
correlation between SERT polymorphisms and autism. Finally, autism is
considered a brain disorder, but studies have so far failed to find consistent
serotonergic abnormalities in autistic brains. A simple mathematical model may
account for these paradoxes, if one assumes that autism is associated with the
failure of a molecular mechanism that both regulates 5-HT release from gut
enterochromaffin cells and mediates 5-HT signaling in the brain. Some 5-HT
receptors may play such a dual role. While the failure of such a mechanism may
lead to consistent abnormalities of synaptic transmission with no alteration of
brain 5-HT levels, its effects on blood 5-HT levels may appear paradoxical.
A great all-in-one overview
If you only
want to read one paper on serotonin and autism, and one that is not too science
heavy, the one for you is:-
If you have
more interest, then read on …
Research on Serotonin in the Autistic
Brain
A recurring
problem in all brain research is the lack of physical samples. You cannot just open up someone's head and take
a brain biopsy. Research is either
carried out on the tiny number of autistic brains donated to medical research,
or it is non-invasive (MRIs and EEGs etc.), or it is very indirect. An example of this latter type is the
following paper from Belgium, home of kriek, a beer made from cherries and
French fries served with mayonnaise.
"Some
studies have suggested that disorders in the central serotonergic function may
play a role in the pathophysiology of autistic disorder. In order to assess the
central serotonergic turnover in autism, this study examines the cortisol and
prolactin responses to administration of L-5-hydroxy-tryptophan (5-HTP), the
direct precursor of 5-HT in 18 male, post-pubertal, Caucasian autistic patients
(age 13-19 y.; I.Q.>55) and 22 matched healthy volunteers. Serum cortisol
and prolactin were determined 45 and 30 minutes before administration of 5-HTP
(4 mg/kg in non enteric-coated tablets) or an identical placebo in a single
blind order and, thereafter, every 30 minutes over a 3-hour period. The
5-HTP-induced increases in serum cortisol were significantly lower in autistic
patients than in controls, whereas there were no significant differences in
5-HTP-induced prolactin responses between both study groups. In baseline
conditions, no significant differences were found in serum cortisol and
prolactin between autistic and normal children. The results suggest that autism
is accompanied by a central serotonergic hypoactivity and that the latter could
play a role in the pathophysiology of autism."
Tryptophan and DHEA
Just to
complicate things a little further, I now introduce you to Tryptophan and
DHEA.
Tryptophan is an essential amino acid, meaning that it is essential for human life,
cannot be synthesized by the organism, and therefore must be part of your diet.
Tryptophan functions as a biochemical precursor for the
following compounds:- Serotonin, synthesized via tryptophan hydroxylase. Serotonin, in turn,
can be converted to melatonin (a neurohormone).
- Niacin is synthesized from
tryptophan via kynurenine and quinolinic acids as key biosynthetic
intermediates
- Auxin (a phytohormone) when sieve
tube elements undergo apoptosis tryptophan is
converted to auxins
The disorders fructose malabsorption and lactose intolerance cause improper absorption of tryptophan in the intestine, reduced levels of tryptophan in the blood and depression
What you
will not find on Wikipedia, is that perhaps Tryptophan is in fact also a bona
fide neurotransmitter in its own right.
Tryptophan as an evolutionarily conserved signal to brain serotonin: molecular evidence and psychiatric implications.
Abstract
The role of serotonin (5-HT) in
psychopathology has been investigated for decades. Among others, symptoms of
depression, panic, aggression and suicidality have been associated with
serotonergic dysfunction. Here we summarize the evidence that low brain 5-HT
signals a metabolic imbalance that is evolutionarily conserved and not specific
for any specific psychiatric diagnosis. The synthesis and neuronal release of brain 5-HT depends
on the concentration of free tryptophan in blood and brain because the
affinity constant of neuronal tryptophan hydroxylase is in that concentration
range. This relationship is evolutionarily conserved. Degradation of tryptophan, resulting in lower
blood levels and impaired cerebral production and release of serotonin, is
enhanced by inter alia inflammation,
pregnancy and stress in all species investigated, including humans.
Consequently, tryptophan may not only serve as a nutrient, but also as a bona
fide signaling amino acid. Humans
suffering from inflammatory
and other somatic diseases accompanied by low tryptophan levels, exhibit
disturbed social behaviour, increased irritability and lack of impulse control,
rather than depression. Under particular circumstances, such behaviour
may have survival value. Drugs that increase brain levels of serotonin may
therefore be useful in a variety of psychiatric disorders and symptoms
associated with low availability of tryptophan.
This paper is
open access, it gets quite technical but here is a summary of the conclusion.
Our findings support a possible
mitochondrial dysfunction as a result of impaired tryptophan metabolism in
cells from patients with ASDs
Although approximately 99% of the
dietary tryptophan intake is metabolized via the kynurenine pathway, tryptophan
is also the main precursor for both serotonin and melatonin
Melatonin plays a critical role
in the regulation of the circadian rhythm, and anomalies of this rhythm have
been associated with some of the signs in the autistic spectrum, like seizures
or sleep disorders
Serotonin is a neurotransmitter
involved in multiple aspects of brain functions, ranging from the regulation of
mood to the control of appetite and social interactions and its production has
been reported as deficient in ASD brains.
Tryptophan levels have been
demonstrated to directly influence central nervous system (CNS) serotonin
levels and behavior, and altered tryptophan transport has been described in
fibroblasts from boys with attention deficit/hyperactivity disorder (ADHD)
Patients with ASDs, on average,
are less capable of utilizing tryptophan as an energy source than controls.
Decreased tryptophan metabolism
in patients with ASDs may alter metabolic pathways involved in the regulation
of the early stages of brain development (first month of gestation),
mitochondrial homeostasis and immune system activity in the brain.
Disruption of such pathways can
primarily be caused either by insufficient serotonin production by placental
cells, mitochondrial dysfunction and/or impaired balance between quinolinic and
kynurenic acid in fetal cells. The combined effects of these events could lead
to abnormal organization of neurons , particularly in specific brain regions,
determining the imbalance between the short- and long-term circuitry that has
been considered to be one of the fundamentals of the ASD neuropathology
Even though the ideal target
tissue, brain, could not be investigated, our observation of decreased
tryptophan metabolism in cells from patients with ASDs may provide a unifying
model that could help explain the genetic heterogeneity of ASDs.
Tryptophan is a precursor of important
compounds, such as serotonin, quinolinic acid, and kynurenic acid, which are
involved in neurodevelopment and synaptogenesis. In addition, quinolinic acid
is the structural precursor of NAD+, a critical energy carrier in
mitochondria. Also, the serotonin branch of the tryptophan metabolic pathway
generates NADH. Lastly, the levels of quinolinic and kynurenic acid are
strongly influenced by the activity of the immune system. Therefore, decreased tryptophan
metabolism may alter brain development, neuroimmune activity and mitochondrial
function. Our finding of decreased tryptophan metabolism appears to
provide a unifying biochemical basis for ASDs and perhaps an initial step in
the development of a diagnostic assay for ASDs.
DHEA
DHEA (didehydroepiandrosterone) It
is the most abundant circulating steroid in humans, importantly for us to know
it is also produced in the brain. It has
a variety of potential biological effects in its own right, binding to an array
of nuclear and cell surface and acting as a neurosteroid.Faulty serotonin--DHEA interactions in autism: results of the5-hydroxytryptophan challenge test.
Abstract
BACKGROUND:
Autism is accompanied by peripheral and
central disorders in the metabolism of serotonin (5-HT). The present study
examines plasma dehydroepiandrosterone-sulphate (DHEA-S) and the
cortisol/DHEA-S ratio following administration of L-5-hydroxytryptophan
(5-HTP), the direct precursor of 5-HT, to autistic patients.
METHODS:
Plasma DHEA-S levels were determined
both before and after administration of 5-HTP or placebo, on two consecutive
days in a single blind order in 18 male autistic patients and 22 matched
healthy controls.
RESULTS:
The 5-HTP-induced DHEA-S responses were
significantly higher in autistic patients than in controls. In baseline
conditions, the cortisol/DHEA-S ratio was significantly higher in autistic
patients than in controls. Discussion: The results suggest that autism is accompanied by a major
disequilibrium in the serotonergic system. The increased Cortisol (neurotoxic)
versus DHEA-S (neuroprotective) ratio suggests that an increased neurotoxic
potential occurs in autism.
CONCLUSIONS:
It
is concluded that disequilibrium in the peripheral and central turnover of
serotonin and an increased neurotoxic capacity by glucocorticoids are important
pathways in autism.
Mice Studies
For the mice
lovers amongst you, they also get their vitamin P (Prozac).
Serotonin Defects Identified in "Autistic" Mice
Serotonin modulators mitigate
some BTBR behaviors
The researchers tested the effects of acute doses of fluoxetine (Prozac)
(an SERT blocker), risperidone (a 5-HT2A receptor antagonist), and
buspirone (a partial 5-HT1A receptor agonist) on social and
repetitive behaviors of BTBR mice. These three compounds regulate serotonin
activity and have inconsistent, limited, and sometimes harmful effects in
rodent models of and people with autism. Only buspirone and fluoxetine were
found to make BTBR mice significantly more social: treated mice spend
proportionally more time socializing with a strange mouse than do
saline-treated controls. Interestingly, BTBR mice treated with either buspirone
or fluoxetine show a reduced interest in social novelty: when introduced to a
second stranger mouse, they do not show a preference for either stranger. In
contrast, the saline-treated controls spend more time investigating the newer
mouse. Compared to either buspirone- or fluoxetine-treated mice and
saline-treated controls, Risperidone-treated mice spend less time investigating
strange mice and novel surroundings.
Regardless of treatment, BTBR mice spend comparable amounts of time
burying marbles (an index of repetitive behavior). However, eliminating from
the analysis one saline-treated control that did not bury any marbles suggests
that risperidone-treated mice bury significantly fewer marbles than the
saline-treated controls.
In summary, Daws and her team concluded that the autism-like behaviors
of BTBR mice are likely due in part to an altered hippocampal SERT serotonin
transporter and/or an altered 5-HT1A serotonin receptor. These
findings may lead to the identification of additional therapeutic targets for
treating human autism.
Conclusion
There was a
lot of science in this post and it was clear that the mechanisms involved are only
very partially understood by researchers.
It is clear
that interventions increasing central (brain) serotonin levels are likely to
reduce autistic behaviours. Prozac was
mentioned, but there is a much wider class of drugs called serenic, many of
which could potentially be helpful. As
mentioned earlier, the big problem with most of the drugs created for
psychiatrists is side effects. Autism is
supposed to be very common, but you would not think so by looking at way new
drugs are developed. As a result, the
drugs currently used in ASD and the majority of those in the pipeline are ones developed
for other conditions (depression, bi-polar, psychosis , anxiety, ADHD, schizophrenia, Alzheimer’s etc.) many of which share some similar
characteristics, but are essentially different conditions, with the exception
of ADHD. It is akin to trying to fix
your Ford car with a parts bin filled with Toyota components; it is possible,
but not a wise idea.
In my opinion,
all the hormone dysfunctions in autism can eventually be traced back to damage
caused by oxidative stress and neuroinflammation. The brain has just adjusted to find a new
homeostasis, which happens to be an autistic one. The list of metabolic disturbances in autism is
long and getting longer; but they are just consequences. I very much doubt it is ever going to be possible
to go hormone by hormone, neurotransmitter by neurotransmitter “correcting”
them. I think the best solution is to go further
back up the chain and look at how hormones and neurotransmitters themselves are
jointly regulated. I do not believe
anyone fully understands the molecular basis on which this is carried out, but
as I have pointed out earlier in this blog, you can get the right answer for
the wrong reasons and also without showing your workings. As long as it works, perhaps understanding
why does not matter. A much less intellectual
approach might indeed prove effective.
I will
continue with my problem solving, but less intellectual, approach and see where
it leads.Evidence That Oxytocin Exerts Anxiolytic Effects via Oxytocin Receptor Expressed in Serotonergic Neurons in Mice
"It is thus possible that oxytocin modulates not only anxiety-related behavior but also social behavior via serotoninergic transmission. These observations may provide new insights into psychiatric disorders associated with disruptions in social and emotional behavior, including autism, anxiety disorders, and depression."