This post is about monoamine neurotransmitter disorders in Autism, that are usually a down-stream consequence of other miscellaneous dysfunctions, which makes them “secondary” dysfunctions.
There was a post on this blog way back in 2013 on catecholamines:
Classical monoamine is a broader term and encompasses:-
· Classical Tryptamines:
Drugs used to increase or reduce the effect of monoamines are sometimes used to treat patients with psychiatric disorders, including depression, anxiety, and schizophrenia.
This blog does go on rather ad nauseam about histamine, so today it will skip over it. It does not cause autism, but it certainly can make it much worse in some people.
Tryptophan is a precursor to the neurotransmitters serotonin and melatonin. For years it has been known that odd things are going on in some people with autism regarding tryptophan, serotonin and indeed melatonin. This research does not really lead you anywhere.
Other than being converted to serotonin and melatonin, tryptophan has the potential to be converted in the gut into some very good things and some bad ones; this all depends on what bacteria are present. People lucky enough to have Clostridium sporogenes will produce a super potent, but apparently very safe, antioxidant called 3-Indolepropionic acid (IPA), which is seen as an Alzheimer’s therapy. To be effective you would need a constant supply of IPA, and that is exactly what you get from the right bacteria living in your gut.
Some people with autism have high levels of serotonin in their blood and so do their parent(s). It is known that in the brain many people with autism have low levels of serotonin. Various mechanisms have been proposed to explain this using the body’s feedback loops, including mother to child.
Many people with autism take 5-HTP which is an intermediate in the synthesis of both serotonin and melatonin from tryptophan.
Serotonin itself does not cross the blood brain barrier (BBB).
Too much serotonin in your brain has a negative effect and so taking too much 5-HTP supplement produces negative effects.
Many people take melatonin at small doses for sleep. At larger doses it has many other beneficial effects that range from resolving GI problems to reducing oxidative stress in mitochondria.
Of the Catecholamines, it is dopamine that gets the most attention in neuro-psychiatric disorders and schizophrenia in particular.
There is a dopamine hypothesis for schizophrenia, but there is also a glutamate hypothesis of schizophrenia.
If you read the research, it is actually ADHD that has the strongest connection to dopamine. When you look closer still, you will see that even that connection is quite weak.
The conclusion is that ADHD, just like autism and schizophrenia is usually multigenic, meaning that numerous little things went awry, rather than one single dysfunction.
Tourette's syndrome and related tic disorders may be associated with either too much dopamine or overly sensitive dopamine receptors.
It is fair to say that secondary monoamine neurotransmitter disorders can occur in autism, ADHD and indeed schizophrenia.
There is a long list of primary monoamine neurotransmitter disorders and much is known about them.
Monoamine Neurotransmitter Disorders
I found an excellent paper that tells you pretty much all you could want to know about monoamine neurotransmitter disorders. It also has nice graphics to explain what is going on.
Most people with autism are unlikely to have a primary disorder, but if they did, treating it should have a big impact on them.
BH4 =tetrahydrobiopterin. TH-D=tyrosine hydroxylase deficiency. AADC-D=aromatic L-amino acid decarboxylase deficiency. DTDS=dopamine transporter deficiency syndrome. PLP-DE=pyridoxal-phosphate-dependent epilepsy. P-DE=pyridoxine-dependent epilepsy. AD GTPCH-D=autosomal dominant GTP cyclohydrolase 1 deficiency. SR-D=sepiapterin reductase deficiency. AR GTPCH-D=autosomal recessive GTP cyclohydrolase 1 deficiency. PTPS-D=6-pyruvoyltetrahydropterin synthase deficiency. DHPR-D=dihydropteridine reductase deficiency. HIE=hypoxic ischaemic encephalopathy. PKAN=pantothenate kinase associated neurodegeneration. DNRD=dopa non-responsive dystonia. PKD=paroxysmal kinesogenic dyskinesia.
People with a secondary disorder would typically be identified by testing their spinal fluid for the metabolites of the monoamine. So for serotonin you measure 5-HIAA (5-hydroxyindoleacetic acid) and for dopamine you measure HVA (homovanillic acid).
Figure 2: The monoamine neurotransmitter biosynthesis pathway BH4 is synthesized in four enzymatic steps from GTP. BH4 is a necessary cofactor for TrpH and TH, the rate limiting enzymes in monoamine synthesis. Tryptophan is converted to 5-HTP by TrpH. Tyrosine is converted to L-dopa by TH. The conversion of 5-HTP to serotonin and of L-dopa to dopamine is catalyzed by AADC and its cofactor PLP. When BH4 acts as a cofactor for TH and TrpH, it is converted to PCBD, which in turn is converted to BH4 (in the BH4 regeneration pathway) by a two-step process involving PCD and DHPR. After synthesis, uptake of monoamine neurotransmitters into the synaptic secretory vesicles requires the vesicular monoamine transporter VMAT (not shown).⁶ After synaptic transmission, serotonin and dopamine are metabolised through similar pathways, which involve MAO enzymes and COMT. Presynaptic reuptake of the monoamines is facilitated by DAT and SERT (not shown).⁷ Metabolic pathway of BH4 synthesis is shown in light blue, monoamine synthesis in light green, monoamine catabolism in dark blue, and BH4 regeneration in red. The biogenic amines are illustrated in light green circles and the cofactors (BH4 and PLP) are represented by light blue circles. Enzymes in the monoamine neurotransmitter pathway are underlined. GTPCH=GTP cyclohydrolase 1. H₂NP₃=dihydroneopterin triphosphate. PTPS=6-pyruvoyltetrahydropterin synthase. 6-PTP=6-pyruvoyltetrahydropterin. AR=aldose reductase. SP=sepiapterin. SR=sepiapterin reductase. BH4 =tetrahydrobiopterin. TrpH=tryptophan hydroxylase. TH=tyrosine hydroxylase. DHPR=dihydropteridine reductase. PCBD=tetrahydrobiopterin-α-carbinolamine. PCD=pterin-4αcarbinolamine dehydratase. qBH₂=(quinonoid) dihydrobiopterin. 5-HTP=5-hydroxytryptophan. L-dopa=levodihydroxyphenylalanine. COMT=catechol-O-methyltransferase. 3-OMD=3-ortho-methyldopa. VLA=vanillactic acid. AADC=aromatic L-amino acid decarboxylase. PLP=pyridoxal phosphate. DBH=dopamine β hydroxylase. PNMT=phenylethanolamine N-methyltransferase. MAO=monoamine oxidase. AD=aldehyde dehydrogenase. 3-MT=3-methoxytyramine. DOPAC=3,4-dihydroxyphenylacetic acid. 5-HIAA=5-hydroxyindoleacetic acid. HVA=homovanillic acid. MHPG=3-methoxy-4-hydroxylphenylglycol. VMA=vanillylmandelic acid.
The paper is very clear about what to:-
Secondary neurotransmitter disorders
Neurotransmitters abnormalities indicative of dopamine or serotonin depletion are becoming increasingly recognized as secondary phenomena in several neurological disorders. Concentrations of HVA and 5-HIAA in CSF in such patients are mostly within the range deemed abnormal for primary neurotransmitter disorders, but generally do not reach the lowest levels.
A secondary reduction in HVA is reported in perinatal asphyxia, disorders of folate metabolism, phenyl ketonuria, Lesch-Nyhan disease, mitochondrial disorders, epilepsy (and infantile spasms), opsoclonus-myoclonus, pontocerebellar hypoplasia, leukodystrophies, Rett’s syndrome, and some neuropsychiatric disorders. Many patients who have no specific diagnosis but who present with neuromuscular or dystonic symptoms have low HVA concentrations in CSF, which suggests dopaminergic depletion. These patients also often present with dyskinesia, tremor, and eye-movement disorders similar to those seen in many of the primary monoamine neurotransmitter disorders. Cortical atrophy is associated with low levels of 5-HIAA in CSF. Low concentrations of HVA and 5-HIAA have been reported in patients with type 2 pontocerebellar hypoplasia and in a syndrome that involves spontaneous periodic hypothermia and hyperhidrosis. Whether the latter syndrome is a primary or secondary neurotransmitter disorder is still unclear because the underlying cause is unknown. Patients with neonatal disease onset who have severe motor deficits and abnormalities on brain MRI seem particularly vulnerable to secondary reductions in HVA production. Such disruption of normal brain function is likely to impair biogenic monoamine synthesis, and the resultant neurotransmitter deficiencies in critical periods of neurodevelopment are thought to prevent development of certain brain functions. The possibility of treating such patients with levodopa, 5-hydroxytryptophan, or both should be considered, therefore, to improve brain maturation and neurological outcome.
When you look at autism specifically it is usually 5-HIAA and not HVA that is disturbed.
Now for two papers by one of our reader Roger’s favourite researchers, Vincent Ramaekers. Ramaekers is one of the specialists for central folate deficiency and even better is a researcher/clinician who replies to my emails.
Background
Patients with autism spectrum disorder (ASD) may have low brain serotonin concentrations as reflected by the serotonin end-metabolite 5-hydroxyindolacetic acid (5HIAA) in cerebrospinal fluid (CSF).
Methods
We sequenced the candidate genes SLC6A4 (SERT), SLC29A4 (PMAT), and GCHFR (GFRP), followed by whole exome analysis.
Results
The known heterozygous p.Gly56Ala mutation in
the SLC6A4 gene was equally found in the ASD and control populations.
Using a genetic candidate gene approach, we identified, in 8 patients of a
cohort of 248 with ASD, a high prevalence (3.2%) of three novel heterozygous
non-synonymous mutations within the SLC29A4 plasma membrane monoamine
transporter (PMAT) gene, c.86A > G (p.Asp29Gly) in two patients,
c.412G > A (p.Ala138Thr) in five patients, and c.978 T > G
(p.Asp326Glu) in one patient. Genome analysis of unaffected parents confirmed
that these PMAT mutations were not de novo but inherited mutations.
Expression of mutations PMAT-p.Ala138Thr and
p.Asp326Glu in cellulae revealed significant reduced transport uptake
activity towards a variety of substrates including serotonin, dopamine, and
1-methyl-4-phenylpyridinium (MPP+), while mutation p.Asp29Gly had
reduced transport activity only towards MPP+. At least two ASD
subjects with either the PMAT-Ala138Thr or the PMAT-Asp326Glu mutation with
altered serotonin transport activity had, besides low 5HIAA in CSF, elevated
serotonin levels in blood and platelets. Moreover, whole exome sequencing
revealed additional alterations in these two ASD patients in mainly
serotonin-homeostasis genes compared to their non-affected family members.
Conclusions
Our findings link mutations in SLC29A4 to the ASD population although not invariably to low brain serotonin. PMAT dysfunction is speculated to raise serotonin prenatally, exerting a negative feedback inhibition through serotonin receptors on development of serotonin networks and local serotonin synthesis. Exome sequencing of serotonin homeostasis genes in two families illustrated more insight in aberrant serotonin signaling in ASD.
In this context, we found that isolated low brain serotonin concentration, as reflected by the 5HIAA in the CSF, is associated with PDD-NOS and the functional (heterozygous) c.167G > C (p.G56A) mutation of the serotonin re-uptake transporter gene (SERT/SCL6A4) combined with a homozygous long (L/L) SERT gene-linked polymorphic promoter (5-HTTLPR) region [21]. Moreover, daily treatment with serotonin precursor 5-hydroxytryptophan and aromatic amino acid decarboxylase (AADC) inhibitor carbidopaled to clinical improvements and normalization of the 5HIAA levels in the CSF and urine, indicating that the brain serotonin turnover was normalized [22]. In an attempt to gain some insight into the brain serotonin physiology and underlying mechanisms of abnormal brain metabolism, we report in patients with ASD and low brain 5HIAA mutations in the serotonin transporter SCL29A4, an observation that may provide some bases for improving the application of various therapeutic tools.
Whole blood serotonin and platelet serotonin content are increased in about 25 to 30% of the ASD population and their first-degree relatives. Because the fetal blood–brain barrier during pregnancy is not yet fully formed, the fetal brain will be exposed to high serotonin levels, leading through a negative-feedback mechanism to a loss of serotonin neurons and a limited outgrowth of their terminals. This hypothesis has been confirmed by rat studies using the serotonin agonist 5-methoxytryptamine between gestational days 12 until postnatal day 20 [42].
Tryptophan hydroxylase (TPH; EC 1.14.16.4) catalyzes the first rate-limiting step of serotonin biosynthesis by converting l-tryptophan to 5-hydroxytryptophan. Serotonin controls multiple vegetative functions and modulates sensory and alpha-motor neurons at the spinal level. We report on five boys with floppiness in infancy followed by motor delay, development of a hypotonic-ataxic syndrome, learning disability, and short attention span. Cerebrospinal fluid (CSF) analysis showed a 51 to 65% reduction of the serotonin end-metabolite 5-hydroxyindoleacetic acid (5HIAA) compared to age-matched median values. In one out of five patients a low CSF 5-methyltetrahydrofolate (MTHF) was present probably due to the common C677T heterozygous mutation of the methylenetetrahydrofolate reductase (MTHFR) gene. Baseline 24-h urinary excretion showed diminished 5HIAA values, not changing after a single oral load with l-tryptophan (50-70 mg/kg), but normalizing after 5-hydroxytryptophan administration (1 mg/kg). Treatment with 5-hydroxytryptophan (4-6 mg/kg) and carbidopa (0.5-1.0 mg/kg) resulted in clinical amelioration and normalization of 5HIAA levels in CSF and urine. In the patient with additional MTHFR heterozygosity, a heterozygous missense mutation within exon 6 (G529A) of the TPH gene caused an exchange of valine by isoleucine at codon 177 (V177I). This has been interpreted as a rare DNA variant because the pedigree analysis did not provide any genotype-phenotype correlation. In the other four patients the TPH gene analysis was normal. In conclusion, this new neurodevelopmental syndrome responsive to treatment with 5-hydroxytryptophan and carbidopa might result from an overall reduced capacity of serotonin production due to a TPH gene regulatory defect, unknown factors inactivating the TPH enzyme, or selective loss of serotonergic neurons.
Carbidopa is a drug given to people with Parkinson's disease in order to inhibit peripheral metabolism of levodopa. This property is significant in that it allows a greater proportion of peripheral levodopa to cross the blood–brain barrier for central nervous system effect.
L-DOPA/levodopa is the precursor to the neurotransmitters dopamine, norepinephrine (noradrenaline), and epinephrine (adrenaline) collectively known as catecholamines. Furthermore, L-DOPA itself mediates neurotrophic factor release by the brain and CNS. As a drug, it is used in the clinical treatment of Parkinson's disease.
Abstract
Based upon the hypothesis that brain monoamine metabolism is disorganized in some children with an autistic disorder, we tried low dose levodopa therapy (0.5 mg/kg/day) proposed by Segawa, et al. We treated 20 patients with an autistic disorder diagnosed according to DSM-IV, and evaluated the effectiveness. A double blind cross over method was applied in this study because of the small number of patients. Drug effects were observed carefully by the psychologists and pediatric neurologists using an evaluation sheet consisting of twenty items. No significant effectiveness was observed in this study, although four cases (20%) showed some improvement. In conclusion, administration of low dose levodopa to autistic children resulted in no clear clinical improvements of autistic symptoms.
A team led by Wen-Hann Tan, of the Genetics Program at Children’s, is completing a phase I clinical trial examining the safety and dosing of levodopa, a drug commonly used for Parkinson disease, in patients with Angelman syndrome. The results will inform a planned phase II treatment trial, to be conducted in collaboration with University of California San Francisco, University of California San Diego, Vanderbilt University, Baylor College of Medicine and Greenwood Genetic Center. [For more information on Angelman research and events, check out this Facebook page.]
Research suggests that levodopa may increase the activity of an important brain enzyme known as CaMKII, which is involved in learning and memory, and that may be decreased in Angelman syndrome. In a mouse model of Angelman syndrome, low activity of CaMKII is associated with neurologic defects. Levodopa reverses the chemical modification that underlies decreased CaMKII activity. When this same modification is reversed in mice by genetic means, they show improvement in neurologic deficits, and it’s hoped that levodopa can do the same in humans.
Parkinson's disease
We saw in an earlier post that people with Down Syndrome are prone to early onset Alzheimer’s. In the case of lack of dopamine the risk might be towards Parkinson's disease (PD).
There was a recent post on PANS/PANDAS/Tourette’s which like PD results from dysfunction in the basal ganglia region of the brain.
The basal ganglia, a group of brain structures innervated by the dopaminergic system, are the most seriously affected brain areas in PD. The main pathological characteristic of PD is cell death in the substantia nigra, where greatly reduced activity of dopamine-secreting cells caused by cell death.
When a decision is made to perform a particular action, inhibition is reduced for the required motor system, thereby releasing it for activation. Dopamine acts to facilitate this release of inhibition, so high levels of dopamine function tend to promote motor activity, while low levels of dopamine function, such as occur in PD, demand greater exertions of effort for any given movement. Thus, the net effect of dopamine depletion is to produce hypokinesia, an overall reduction in motor output. Drugs that are used to treat PD, conversely, may produce excessive dopamine activity, allowing motor systems to be activated at inappropriate times and thereby producing dyskinesias.
The drugs used in PD only treat some of the symptoms and are not curative, but do offer effective ways to increase dopamine levels.
High rates of Parkinsonism in adults with autism? Or is it partly drug-induced Parkinsonism
There is a study suggesting high rates of Parkinsonism in adults with autism. I think some of this is more likely to be drug-induced Parkinsonism, either caused by currently taken drugs, or those taken in earlier years, which is not mentioned in the study.
Background
While it is now recognized that autism spectrum disorder (ASD) is typically a life-long condition, there exist only a handful of systematic studies on middle-aged and older adults with this condition.
Methods
We first performed a structured examination of parkinsonian motor signs in a hypothesis-generating, pilot study (study I) of 19 adults with ASD over 49 years of age. Observing high rates of parkinsonism in those off atypical neuroleptics (2/12, 17 %) in comparison to published population rates for Parkinson’s disease and parkinsonism, we examined a second sample of 37 adults with ASD, over 39 years of age, using a structured neurological assessment for parkinsonism.
Results
Twelve of the 37 subjects (32 %) met the diagnostic criteria for parkinsonism; however, of these, 29 subjects were on atypical neuroleptics, complicating interpretation of the findings. Two of eight (25 %) subjects not taking atypical neuroleptic medications met the criteria for parkinsonism. Combining subjects who were not currently taking atypical neuroleptic medications, across both studies, we conservatively classified 4/20 (20 %) with parkinsonism.
Conclusions
We find a high frequency of parkinsonism among ASD individuals older than 39 years. If high rates of parkinsonism and potentially Parkinson’s disease are confirmed in subsequent studies of ASD, this observation has important implications for understanding the neurobiology of autism and treatment of manifestations in older adults. Given the prevalence of autism in school-age children, the recognition of its life-long natural history, and the recognition of the aging of western societies, these findings also support the importance of further systematic study of other aspects of older adults with autism.
Drug induced Parkinsonism
Any drug that blocks the action of dopamine (referred to as a dopamine antagonist) is likely to cause parkinsonism. Drugs used to treat schizophrenia and other psychotic disorders such as behaviour disturbances in people with dementia, known as neuroleptic drugs, are possibly the major cause of drug-induced parkinsonism worldwide. Parkinsonism can occur from the use of any of the various classes of neuroleptics.
The atypical neuroleptics – clozapine (Clozaril) and quetiapine (Seroquel), and to a lesser extent olanzapine (Zyprexa) and risperidone (Risperdal) – appear to have a lower incidence of extrapyramidal side effects, including parkinsonism. These drugs are generally best avoided by people with Parkinson’s, although some may be used by specialists to treat symptoms such as hallucinations occurring with Parkinson’s.
For people with Parkinson’s, anti-sickness drugs such as domperidone (Motilium) or ondansetron (Zofran) are the drugs of choice for nausea and vomiting.
As well as neuroleptics, some other drugs can cause drug-induced parkinsonism. These include some medications for dizziness and nausea such as prochlorperazine (Stemetil); and metoclopromide (Maxalon), which is used to stop sickness and in the treatment of indigestion.
Calcium channel blocking drugs used to treat high blood pressure, abnormal heart rhythm, angina pectoris, panic attacks, manic depression and migraine may occasionally cause drug-induced parkinsonism. Calcium channel blocking drugs are, however, widely used to treat angina and high blood pressure, and it is important to note that most common agents in clinical use probably do not have this side effect. These drugs should never be stopped abruptly without discussion with your doctor.
A number of other agents have been reported to cause drug-induced parkinsonism, but clear proof of cause and effect is often lacking. Amiodarone, used to treat heart problems, causes tremor and some people have been reported to develop Parkinson’s-like symptoms. Sodium valproate, used to treat epilepsy, and lithium, used in depression, both commonly cause tremor which may be mistaken for Parkinson’s.
Dopamine Receptors vs Dopamine as Dysfunctions
We saw in great detail with the neurotransmitter GABA that the autism dysfunctions are usually related to the function and make-up of the neurotransmitter receptors, rather than the amount of GABA itself. Targeting these dysfunctions does indeed deliver results for many people with autism and Asperger’s.
Potentially this might be the case with dopamine, but it looks much less likely.
I did look at the following paper which seeks to link the genes of dopamine receptors (DRD1, DRD2, DRD3, DRD4, DRD5), dopamine-synthesizing enzyme DDC, dopamine transporter (DAT) and dopamine-catabolizing enzymes COMT and MAO to the several hundred known autism genes.
Using bioinformatics, in some they found a link and in others they did not.
The graphic below looks nice, but I am not sure it tells us much useful. To me it looks much better to go direct to the autism gene and then see how to selectively modulate it. I do not think you can assume that the associated dopamine gene/receptor is the unifying problem across dysfunctional autism genes. It would be great if it was.
Autism spectrum disorder (ASD) is a debilitating brain illness causing social deficits, delayed development and repetitive behaviors. ASD is a heritable neurodevelopmental disorder with poorly understood and complex etiology. The central dopaminergic system is strongly implicated in ASD pathogenesis.
Genes encoding various elements of this system (including dopamine receptors, the dopamine transporter or enzymes of synthesis and catabolism) have been linked to ASD. Here, we comprehensively evaluate known molecular interactors of dopaminergic genes, and identify their potential molecular partners within up/down-steam signaling pathways associated with dopamine. These in silico analyses allowed us to construct a map of molecular pathways, regulated by dopamine and involved in ASD. Clustering these pathways reveals groups of genes associated with dopamine metabolism, encoding proteins that control dopamine neurotransmission, cytoskeletal processes, synaptic release, Ca2+ signaling, as well as the adenosine, glutamatergic and gamma-aminobutyric systems. Overall, our analyses emphasize the important role of the dopaminergic system in ASD, and implicate several cellular signaling processes in its pathogenesis.
Fig. 3. Reconstruction of biomolecular pathways related to dopaminergic genes associated with ASD (also see Fig. 2 and Table 2 for details). Known biological interactions between protein products of various genes are shown as complexes or denoted by arrows (sharp – activation, dull – inhibition). Proteins encoded by genes associated with ASD are marked with red (other colors are used here for illustration purposes only, to better distinguish visually between multiple different proteins within the dopaminergic pathways). Clustering of proteins into distinct functional groups is shown by dashed lines.
The strongest evidence for the role of dopamine genes in neuropsychiatric disorders is not in schizophrenia or autism, but in ADHD. As you can see in the paper below, even there the association is weak.
Discussion
Although twin studies demonstrate that ADHD is a highly heritable condition, molecular genetic studies suggest that the genetic architecture of ADHD is complex. The handful of genome-wide scans that have been conducted thus far show divergent findings and are, therefore, not conclusive. Similarly, many of the candidate genes reviewed here (i.e. DBH, MAOA, SLC6A2, TPH-2, SLC6A4, CHRNA4, GRIN2A) are theoretically compelling from a neurobiological systems perspective, but available data are sparse and inconsistent. However, candidate gene studies of ADHD have produced substantial evidence implicating several genes in the etiology of the disorder. The literature published since recent meta-analyses is particularly supportive for a role of the genes coding for DRD4, DRD5, SLC6A3, SNAP-25, and HTR1B in the etiology of ADHD.
Yet, even these associations are small and consistent with the idea that the genetic vulnerability to ADHD is mediated by many genes of small effect.
Conclusion
In the ideal world you would take a sample of spinal fluid and measure 5-HIAA, to look for low brain serotonin and measure HVA for low brain dopamine.
For low serotonin you would give 5-HTP, with Dr Ramaekers suggesting 1mg/kg.
For low dopamine you would give levodopa or carbidopa.
In the real world even blood draws can be problematic so most people will never have their spinal fluid analyzed. Perhaps one day in the future this will be standard practice after an autism diagnosis, with numerous test being run at the same time and justifying this invasive procedure. Many blood tests tell you little about brain disorders because the blood brain barrier means that the levels outside the brain will be completely different to those inside the brain. Measuring spinal fluid should be a good proxy for inside the brain.
The research suggests that 1mg/kg of 5-HT could have a long term beneficial effect, particularly if given from a very early age, in those with low serotonin in their brains, which is a large group of autism.
There are 5 types of dopamine receptors and in some genetic disorders the receptors’ response can be up/down regulated. That would trigger a chain reaction with the non dopamine neurotransmitter receptors that are known to interact with that type of dopamine receptor.
There are associations between some autism genes and some dopamine genes, but it looks much more fruitful to target the autism genes themselves.
Avoid drug induced Parkinson’s Disease and other drug induced disorders, by very selective use of drugs.
