Serotonin autism

In order to determine whether there are brain serotonergic abnormalities in children with autism, serotonin synthesis capacity was measured in vivo with PET, using alpha[ C]methyl-L-tryptophan as the tracer. Two different types of serotonergic abnormalities were measured in children with autism (Chugani et al., 1997, 1999 Chandana et al., 2005). The first is a difference in whole brain serotonin... 

Patients with autism have decreased serotonin, dopamine, nicotine, and other neurotransmitters in certain regions of the brain, but no single abnormality. Chugani (2004) examined the evidence for anomalous development of the serotonin system in the brain of children with autism. Serotonin levels in the blood are often elevated in children with autism. Serotonin synthesis is decreased in the frontal region and thalamus on one side of the brain and increased in the dentate nucleus of the opposite cerebellum. 

Since no consistent differences in serotonergic catabolism or metabolism have been identified in autism, yet a substantial proportion of autistic people have increased concentrations of platelet serotonin, attention has turned to the platelets themselves. Platelet irregularities may include increased platelet exposure, increased platelet volume or enhanced platelet uptake and storage, of serotonin. By measuring the concentration of plasma free levels of serotonin, it is possible to assess whether the platelet is exposed to elevated lev-... 

There is as yet little evidence of specific association between abnormal serotonin activity and any of the key cognitive features of autism. More circumscribed study of particular cognitive functions of autism may yet yield new insights. Perhaps most promisingly, the findings of associations between serotonin functioning and obsessional behaviour indicate the need for further investigation. 

The peptide, melatonin, has been implicated in autism. Excess melatonin is thought to decrease learning, memory, attention, emotionality, motivation and pain responses (reviewed Chamberlain Herman, 1990)—all behaviours that are abnormal in autism. Melatonin, released from the pineal gland, is implicated in controlling serotonin and POMC (proopiomelanocortin) peptides, such as beta-endorphin, and an elevation may contribute to, or cause, the serotonin and opioid abnormalities (Chamberlain Herman, 1990). 

The conventional antipsychotics have little effect on the negative psychotic symptoms such as autism, stupor and emotional withdrawal. The so-called atypical antipsychotics, or second-generation antipsychotics, like the heterocyclic compound risperidone, the benzamide sulpiride and several diben-zepines of which clozapine is the best known, have a broader spectrum which means that they also have an effect on the negative psychotic symptoms. Most share a common attribute of working on serotonin receptors as well as dopamine receptors. They have a low risk of extrapyramidal side effects. 

Based on existing findings, there are many important hypotheses in pediatric psychopharmacogenetics. Selective serotonin transporter inhibitors have been shown to have efficacy in double-blind studies in children and/ or adolescents in the treatment of autism, major depression, OCD, and anxiety disorders. Given the association of the serotonin transporter promoter variant with SSRI treatment response in adult depression (Smeraldi et ah, 1998), all of the SSRI-responsive phenotypes should be tested for promoter variant influence on response using family-based or population-based controlled association studies. The report of strong 5-HTTLPR allelic effects on SSRI-induced mania (Mundo et ah, 2000) is of special interest given frequent SSRI-induced activation in children. 

The preliminary findings of a relationship between serotonin S-HTja receptor genotype and atypical antipsychotic responsiveness in schizophrenia warrant replication and could be extended to children and adolescents with autism. Investigation along these lines has been included in the (National Institute of Mental Health (NIMH)-sponsored multicenter study of risperidone in autism (Arnold et ah, 2000). 

Anderson, G.M., Gutknecht, L., Cohen, D.J., Brailly-Tabard, S., and Cohen, J.H.M., Ferrari, P., Roubertoux, P.L., and Tordjman, S. (2002) Serotonin transporter promoter variants in autism functional effects and relationship to platelet hyperserotonemia. Mol Psychiatry 2001 in press. 

Klauck, S.M., Poustka, F., Benner, A., Lesch, K.-P., and Poustka, A. (1997) Serotonin transporter (S-HTT) gene variants associated with autism Hum Mol Genet 6 2233-2238. 

Maestrini, E., Lai, C., Marlow, A., Matthews, N., Wallace, S., Bailey, A., Cook, E., Weeks, D., Monaco, A., and International Molecular Genetics of Autism Consortium. (1999) Serotonin transporter (S-HTT) and gamma-aminobuyric acid receptor subunit beta-3 (GABRB3) gene polymorphisms are not associated with autism in the IMGSA families. Am J Med Genet (Neuropsychiatr Genet), 88 492-496. 

Yirmiya, N., Pilowsky, T., Nemanov, L., Arbelle, S., Feinsilver, T, Fried, I., Ebstein, R.P. (2001) Evidence for an association with the serotonin transporter promoter region polymorphism and autism. Am J Med Genet 105 381-386. 

Serotonin involvement. There is substantial evidence supporting abnormal 5-HT function in autism, particularly with regard to both the social deficit and repetitive behavior dimensions of this disorder. Many studies of the neurobiology of autism have focused on 5-HT, which is implicated in the regulation of many functions relevant to autism, such as learning, memory. 

Abrahamson, R.K., Wright, H.H., Carpenter, R., Brennan, W., Lum-puy, O., Cole, E., and Young, S.R. (1989) Elevated blood serotonin in autistic probands and their first-degree relatives./ Autism Dev Disorder 19 397-407. 

McDougle, C.J., Kresch, L.E., and Posey, D.J. (2000) Repetitive thoughts and behavior in pervasive developmental disorders treatment with serotonin reuptake inhibitors. J Autism Dev Disord 30 427-435. 

Carlsson, M.L. (1998) Hypothesis is infantile autism a hypogluta-matergic disorder Relevance of glutamate-serotonin intetactions for pharmacotherapy. / Neural Transm 105 525—535. 

McDougle, C.J., Posey, D.J., and Potenza, M.N. (in press) Neurobiology of serotonin function in autism. In Hollander, E. and Delaney, K., eds. Diagnosis and Treatment of Autism. New York Marcel Dekker. 

There has been an increasing interest in the use of serotonin reuptake inhibitors (SSRIs) in the treatment of autism (McDougle et al., 1996). Serotonin binds to several types of receptors including the 5-HT2, and 5-HTlc receptors, which are linked to inositol signaling. A double-blind crossover study was completed at a dose of 200 mg/kg per day, and the results demonstrated no significant improvement on inositol therapy (Levine et al., 1997). 

Keywords Dopamine transporter Norepinephrine transporter Serotonin transporter Polymorphism Attention deficit h5rperactivity disorder Parkinson s disease Addiction Anxiety Depression Autism... 

Cook EH, Leventhtil BL (1996) The serotonin system in autism. Curr Opin Pediatr 8 348-354 Cook EH Jr., Stein MA, Krasowski MD, Cox NJ, Olkon DM, Kieffer JE, Leventhal BL (1995) Association of attention-deficit disorder and the dopamine transporter gene. Am J Hum Genet 56 993-998... 

Hjorth S, Bengtsson HJ, KuUbeig A, Carlzon D, PeUot H, Auerbach SB (2000) Serotonin autoreceptor fimction and antidepressant drug action. J Psychopharmacol 14 177-185 Hollander E, Phillips AT, Yeh CC (2003) Targeted treatments for symptom domains in child and adolescent autism. Lancet 362 732-734... 

Makkonen I, Riikonen R, KokM H, Airaksinen MM, Kmkka JT (2008) Serotonin and dopamine transporter binding in children with autism determined by SPECT. Dev Med Child Neurol 50 593-597... 

Hyperserotonemia has been a consistent finding in subjects with autism, which may be due to activity of serotonin-associated platelet proteins (Hranilovic et al., 2008, 2009). Interestingly, 99% of blood serotonin is contained in platelets (Anderson et al., 1987) and studies have shown that there is an approximate 50% increase in blood-levels of serotonin in subjects with autism vs. controls (McBride et al., 1998). Hypotheses for increased serotonin include increased synthesis of serotonin by tryptophan hydroxylase (TPHl), increased uptake of serotonin into platelets via serotonin transporters (5-HTT), diminished release of serotonin from platelets via serotonin 2A receptor, and decreased breakdown of serotonin by monoamine oxidase (MAOA) (Hranilovic et al., 2008). A study by Hranilovic et al. (2008) identified polymorphisms of tryptophan hydroxylase and MAOA with increased serum serotonin levels. Similarly, haplotype analysis has shown a significant association between polymorphisms of TPHl and increased serotonin in whole blood (Cross et al., 2008). 

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