**5. Catecholamines**

Shown correlation between ASD and serotonin transporter gene and found mutations in genes encode rate-limiting enzyme in the catabolism of L-tryptophan such as 2,3 dioxygenase gene is thought to be responsible for increased serotonin levels [81]. There might be defect in the development of the serotonergic system in patients with ASD. Normally, the serotonin neurotransmitter system follows a pattern of age-related development, for example, develop‐ mental studies of serotonin receptor binding in monkeys showed that increment during infancy and throughout childhood, a prepubertal peak, and eventually slowly reduction during adolescence and early adulthood [82]. In humans at 6 year of age serotonin receptor binding is higher than neonatal period or 13-14 year of age [83]. This dynamic changes are impaired in ASD, at the beginning of childhood low serotonin levels are observed compared to normal baseline, but steadily increased from 2 to 15 years of age and reaches higher than adult levels [84, 85]. In various animal models when effect of higher levels of serotonin investigated particılarly in the development of somatosensory system, the deterioration in the formation of thalamo-cortical sensory circuits were observed [86]. Recently "ASD is a hypo‐ serotonergic condition" hypothesis is worth to discuss. In a study of volunteer postmortem brain tissue of ASD patients examined, and the increase in number of serotonergic axons were

This situation cannot be explained by the hypothesis of compensatory mechanisms which expected to result reduction of serotonergic axons in hyperserotonergic state [88]. In men with ASD, in one side of the brain of frontal region and thalamus, typically synthesis of serotonin was reduced, in opposite side of the brain of cerebellum, and dentate nucleus serotonin has

Several PET and SPECT studies in individuals with ASD has shown serotonin transporter binding amount decreased significantly in various brain regions (frontal cortex, cingulate, thalamus, etc..) [89, 90]. Other study was exhibited that low levels of blood serotonin in mothers of children with ASD compared to normal developing children's mother [91]. In another study, individuals with ASD were shown to have low levels of gene responsible for synthesis of serotonin [92]. Serotonergic drugs, the main symptoms of ASD respond less to treatment, but some are partially effective in the symptomatic treatment of patients with autism. These drugs include selective serotonin reuptake inhibitors (selective serotonin reuptake inhibitör=SSRI), 5-HT 2A receptor antagonists, tricyclic antidepressants and receptor antagonists (dopamin/5-

Mechanism of action of these treatments are unknown, but they are thought to act on the developmental defects in serotonergic pathways such as serotonin synthesis, catabolism, and

As a result, the highest level of evidence for ASD relationship with monoamines is the serotonergic system. Hyperserotonemia in peripheral blood in individuals with ASD, despite the presence of opposite results, has been shown to be present in many studies. Low levels of serotonin in the brain tissue is the common finding of hyposerotonergic and hyperserotonergic hypothesis. Future studies will enlight reson for lower serotonin levels in the brain tissue and

observed [87].

HT) mix.

been shown to be increased [70].

20 Autism Spectrum Disorder - Recent Advances

transport-related dynamic abnormalities [93, 94].

will open new horizons both for diagnosis and treatment.

Evidence for the relationship of dopamine and norepinephrine with ASD was gathered from the studies reported decrease in DBH (Dopamine B Hydroxilase) activity and increased serum norepinephrine levels in children with autism and in their parents [95]. Findings increased catecholamine levels of the blood, urine, and cerebrospinal fluid in children with ASD [96, 97] as well as evidences sugested abnormal dopaminergic activity in the medial prefrontal cortex proposed abnormal cathecolaminergic activity [98]. Another supportive study has shown that, patients with ASD have increased urinary homovalinic acid level which is a degradation product of dopamine [99].

Robinson et al [100] demonstrated, mothers of children with ASD has low serum DBH levels and this interpreted to cause possible risk factor for ASD by creating a non-ideal intrauterine environment (leading to reduced norepinephrine and increased levels of dopamine). Study was done by using positron emission tomography (PET) in high-functioning ASD individuals has enligthened that increased activity of dopamine transporter (DAT) at the orbitofontal cortex region [89]. In a more detail study, Neale BM and his colleagues have found a de novo mutation of DAT gene (SLC6A3] in individuals with ASD [101].
