Insight into Neurodevelopmental Disorders Related to the Imbalance of Monoamine Neuroactive Metabolites and Essential Amino Acids
Journal Title: Biomedical Journal of Scientific & Technical Research (BJSTR) - Year 2018, Vol 4, Issue 1
Abstract
Attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) are classified as neurodevelopmental disorders by DSM-5. ADHD is characterized by the behavioral symptoms including inattention, hyperactivity and impulsivity and also by moderate-to-severe academic and social impairment. In addition, ASD is characterized by impaired social interaction, impaired verbal communication, and repetitive behaviors. Brain monoamines and their neuroactive metabolites are thought to play key roles in neurodevelopmental pathology, but the specifics are still unknown. Here we provide the first evidence of a correlation between inattention, higher levels of 3-methoxy-4- hydroxyphenylglycol (MHPG), and lower levels of homovanillic acid (HVA); between hyperactivity/impulsivity, higher levels of HVA, and lower levels of MHPG; and between autistic symptoms, higher levels of MHPG, and lower levels of 5-hydroxyindoleacetic acid (5-HIAA). These correlations lend support to the hypothesis that monoamine imbalance is the basis of neurodevelopmental impairment. Moreover, recent findings show that inefficient monoamine synthesis induced by lack of essential amino acids, and mutation of the monoamine transporter genes in neurons at the junction between the peripheral and central nervous system, may contribute to the genesis of pathological behavior characteristic of neurodevelopmental disorders. This review aims to describe the main mechanism and further asks whether neurodevelopmental disorders are triggered by generation of essential amino acids, and these key enzymes. Monoamine Imbalance Hypothesis Studies on neurodevelopmental disorders have reported dynamic changes in three monoamine neurotransmitters (i.e., noradrenaline, dopamine, and serotonin) [1,2]. There is an accumulating body of evidence showing that administration of methylphenidate and atomoxetine lead to release and/or inhibition noradrenaline and dopamine uptake in the synaptic cleft and the effective reversal of neurodevelopmental disorders [3]. Moreover, serotonin 2A receptor antagonists (such as risperidone) and dopamine D2 receptor antagonists (such as haloperidol) reduce behavioral pathology in ASD [4]. It is interesting to note that neural-network control of noradrenaline, dopamine, and serotonin is involved in brain function impairment in neurodevelopmental disorders. In addition, to examine the effect of monoamine imbalance on neurodevelopmental disorders, we assessed the levels of urinary and salivary monoamine metabolites [5]. Approximately 60% of MHPG (a noradrenaline metabolite) excreted in the urine is from the central nervous system [6]. The dopamine metabolite HVA in urine [7] and the serotonin metabolite 5-HIAA in urine [8] are transported from the brain via different organic anion transporters located in the blood-brain barrier (BBB). Additionally, we showed that reduction of the serotonin level in the brain by 5,7-dihydroxytryptamine injection correlated with lower levels of 5-HIAA in urine [9]. Thus, it is notable that levels of neuroactive metabolites of monoamines in urine can be used as biomarkers reflecting the activation of monoamine nervous system in the brain, and can be determined non-invasively by using urine and saliva. Some studies show reduced concentrations of urinary MHPG and HVA [10], and also decreased HVA concentration in cerebrospinal fluid (CSF), but not 5-HIAA [11] in ADHD patients relative to healthy controls. However, there are inconsistences; with one study showing that urinary HVA and 5-HIAA concentrations are lower in ADHD patients [12] and another showing that CSF HVA level is higher in ADHD patients [1]. Moreover, studies on ASD have found that CSF levels of MHPG, HVA and 5-HIAA involved with behavioral symptoms are increased in ASD [13]. However, Adamsen et al. [14] have pointed out that CSF levels of 5-HIAA were lower in ASD patients than in healthy controls [14]. On the basis of this evidence, there is a relationship between pathological behavior and monoamine imbalance in neurons at the interface between the peripheral and central nervous systems. The results of our analysis of neuroactive monoamine metabolite levels in urine and saliva indicated that these levels reflect indirectly the activation of the monoamine system in the brain [5,15]. Interestingly, correlations have been recently reported between inattention, higher levels of MHPG, and lower levels of HVA; between hyperactivity/impulsivity, higher levels of HVA, and lower levels of MHPG; and between autistic symptoms, higher levels of MHPG, and lower levels of 5-HIAA [5,15]. For example, serotonin neurons commonly receive sustained excitatory input from noradrenaline neurons, and furthermore regulate the mesolimbic and midbrain dopamine pathways [16]. This crosstalk between noradrenaline, dopamine, and serotonin is predicted to maintain the balance of monoamines in the brain. Here we provide the first evidence that links neurodevelopmental disorders to imbalances in monoamine levels.
Authors and Affiliations
Masatoshi Yamashita, Masakazu Morinaga, Takanobu Yamamoto
Keywords
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- EP ID EP590810
- DOI 10.26717/BJSTR.2018.04.001004
- Views 135
- Downloads 0
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