This article is authored by:
Zheng Jie, Chen Yanhui
Affiliation:
Department of Pediatrics, Fujian Medical University Union Hospital
Edited by:
Su Han
Editorial Team:
Li Yongjun
【Abstract】
Attention deficit hyperactivity disorder (ADHD) is a common neuropsychiatric disorder in children and adolescents, with unclear etiology and pathogenesis. Abnormal expression of monoamine oxidase in the central nervous system leads to altered metabolism of monoamine neurotransmitters, resulting in disrupted dopamine/norepinephrine levels, which is believed to be associated with ADHD behavior. There is an interaction between the monoaminergic system and the hypothalamic-pituitary-adrenal (HPA) axis, and dysfunction of the HPA axis is also considered to be involved in the pathogenesis of ADHD. This article reviews the interaction between monoamine neurotransmitters and HPA axis function in ADHD and its possible mechanisms.
【Keywords】
Attention deficit hyperactivity disorder; Monoamine; Monoamine oxidase; Hypothalamic-pituitary-adrenal axis; Krueppel-like factor 11
Funding Project:
National Natural Science Foundation Project (81371262)
Monoaminergic system and HPA axis dysfunctions in attention deficit hyperactivity disorder
Attention deficit hyperactivity disorder (ADHD) is the most common neuropsychiatric disorder in children and adolescents. Its etiology and pathogenesis are still not clear. The disorder of monoamine oxidase function in the central nervous system can result in abnormal catabolism of monoamine neurotransmitters, leading to alteration of dopamine/norepinephrine levels, which is believed to be associated with ADHD behavior. Besides, dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis is also involved in the pathogenesis of ADHD. In this review, the interaction between the monoaminergic system and HPA axis and its possible mechanism related to ADHD will be systematically summed up based on recent research.
【Key words】
Attention deficit hyperactivity disorder; Monoamine; Monoamine oxidase; Hypothalamic pituitary adrenal axis; Krueppel-like factor 11
Attention deficit hyperactivity disorder (ADHD) is a chronic neurodevelopmental disorder in children and adolescents, characterized by symptoms such as inattention, hyperactivity, and impulsivity, making it the most common behavioral disorder in school-aged children. Its etiology is complex, treatment is difficult, and it has a high incidence with low severity, with a heritability of about 40%［1］.
Numerous studies have shown that the disruption of neurotransmitters in the central nervous system, especially monoamine neurotransmitters, may be an important mechanism in the pathogenesis of ADHD［2］. In recent years, more and more studies have shown a correlation between the hypothalamic-pituitary-adrenal (HPA) axis and the levels of central nervous system monoamine neurotransmitters. Glucocorticoids (GC) can regulate monoamine neurotransmitters through glucocorticoid receptors (GR) and are involved in the pathogenesis of ADHD［3-4］. This article reviews the interaction and possible mechanisms between monoamine neurotransmitters and the HPA axis.
1 The Role of Monoamine Neurotransmitters in the Pathogenesis of ADHD
Monoamine neurotransmitters mainly include adrenaline, norepinephrine (NE), serotonin (5-hydroxyptamine, 5-HT), dopamine, etc., which are widely involved in the regulation of physiological activities and are closely related to neuropsychiatric disorders［2,5］. In ADHD and its common comorbidities, such as conduct disorder and oppositional defiant disorder, neurotransmitters like dopamine, 5-HT, and NE are involved in the pathogenesis［6］.
Dopamine plays a wide role in the brain, participating in numerous activities from regulating movement to controlling attention. Dopamine is mainly secreted in the midbrain and acts on effector cells in the prefrontal cortex, basal ganglia, limbic system, etc., binding to various types of dopamine receptors (DRD) to exert different effects. DRD is divided into five subtypes, including D1 type (DRD1, DRD5) and D2 type (DRD2, DRD3, DRD4). D2 type receptors have received extensive attention in the field of neuropsychiatric disorders, and a large body of evidence suggests that DRD3 is closely related to emotion, cognition, mental state, and motor control［7］. Studies have also found that abnormalities in the coding genes of DRD2, DRD4, and DRD5 are associated with symptoms of ADHD［8-9］.
The importance of dopamine in the pathogenesis of ADHD is increasingly recognized. Maitra et al.［10］ analyzed 148 ADHD families and followed up on the internal phenotypes and age of onset of family members, finding that the homozygous and heterozygous genotypes of the DRD5 gene single nucleotide polymorphism (SNP) rs6283 and rs113828117 were more common in early-onset ADHD patients, suggesting a correlation between DRD5 and the age of onset in ADHD patients. Elbaz et al.［8］ found a correlation between DRD4 gene SNP and the onset of ADHD in an Egyptian population using a similar method. Carriers of the A1 allele of the DRD2 gene have functional abnormalities in brain areas related to the reward mechanism, and the DRD2 gene also affects the thickness of the prefrontal cortex in ADHD patients［9,11］.
Many studies related to potential biomarkers for ADHD have also pointed to dopamine-related transporters, metabolites, etc., such as the dopamine transporter (DAT). The variable number of tandem repeats (VNTR) 10R/10R genotype of the DAT1 gene is associated with childhood ADHD, while the 9R-6R haplotype is associated with adult ADHD. DAT1 VNTR also affects the volume of the striatum with age［12］. An increase in the ratio of homovanillic acid/hydroxyindoleacetic acid in cerebrospinal fluid also reflects abnormalities in DAT［13-14］.
In a report published by the World Federation of Biological Psychiatry and the World ADHD Federation regarding potential biomarkers for ADHD, increased olfactory sensitivity is considered one of the few relatively clear potential biomarkers with significant reference value for diagnosing ADHD［15］. Its structural basis is also believed to be related to dopamine, with the hypothesis suggesting that changes in striatal dopamine function in ADHD patients lead to a reduction in dopaminergic neurogenesis, thereby weakening dopamine inhibition in the olfactory bulb region［16］.
2 Monoamine Oxidase as One of the Key Metabolic Enzymes Regulating Monoamine Neurotransmitters
Metabolic enzymes of monoamine neurotransmitters include monoamine oxidase (MAO), catechol-O-methyltransferase (COMT), etc. MAO mainly catalyzes the oxidative deamination reaction of monoamine neurotransmitters, while COMT mainly catalyzes the methylation reaction of substrates. Dopamine is first deaminated and then methylated under the action of MAO and COMT to produce homovanillic acid; at the same time, it can be converted to NE under the action of dopamine-β-hydroxylase; NE is also metabolized to vanillylmandelic acid by MAO. MAO inhibitors can increase the concentration of monoamine neurotransmitters such as NE, 5-HT, and dopamine in the brain of animals, thereby affecting animal behavior［17］.
MAO is divided into two subtypes, A and B, both of which have similar metabolic capabilities for dopamine. Additionally, MAOB mainly metabolizes phenethylamine and benzylamine, while MAOA is more involved in the metabolism of dopamine, 5-HT, and NE. The MAOA gene is associated with impulsive and aggressive behavior, and patients with Brunner syndrome caused by MAOA gene deficiency exhibit ADHD-like symptoms such as impulsivity, sleep disorders, and low IQ［19］. In patients with severe ADHD, MAO activity is nearly twice that of patients with mild ADHD. EI-Tarras et al.［20］ found that MAOA VNTR 3R/4R and 3R/2R, along with DAT1 VNTR 7R and 11R, are risk factors for ADHD. The longer the MAOA VNTR, the higher the transcriptional activity of MAOA［21］. ADHD patients with longer MAOA VNTR have lower IQ, and for those with longer MAOA VNTR, the efficacy of methylphenidate is more significant. Additionally, in neuropsychological studies, variations in MAOA have been found to be associated with alternative errors, and methylphenidate treatment weakens this association. Individuals with the TT genotype at the MAOA gene SNP rs1137070 have lower MAOA activity, and their manifestations related to ADHD are more pronounced in the prefrontal cortex and insula［22］. Nymberg et al.［23］ also found sex-specific ADHD symptoms related to MAOA and differential responses to the reward circuit, which is also believed to be closely related to the pathogenesis of ADHD［24］.
3 HPA Axis Dysfunction in ADHD Patients
According to Gray’s motivational theory, three interdependent systems are involved in behavior management: the fight/flight system, the incentive or behavioral activation system, and the behavioral inhibition system［25］. Activation of the behavioral inhibition system leads to endocrine responses, including changes in GC levels, and one of the core impairments in ADHD is the abnormality of the behavioral inhibition system. ADHD patients exhibit characteristics such as blunted GC response to stress, low GC awakening response, and low daytime serum GC levels, with a higher GC level/perceived stress ratio［26-27］. These studies suggest that ADHD patients have dysfunction of the HPA axis.
One of the risk factors for the occurrence of ADHD in children is maternal depression during pregnancy, as depression can lead to increased secretion of GC, which can inhibit HPA axis function and induce abnormalities in fetal nervous system development, thereby affecting the ability to respond to stress［28-29］. Yu et al.［30］ found that male adolescents with aggressive behavior had significantly lower GC levels, and their aggression was negatively correlated with GC levels. Popma et al.［31］ and Loney et al.［32］ found in their respective studies that cold-hearted male adolescents had low GC levels, and male adolescents with destructive behavior had lower morning GC levels. This suggests that GC is closely related to the management of individual emotions and behaviors. Chen et al.［3］ found in clinical control studies that ADHD patients had lower GC levels than normal children. Yang et al.［33］ analyzed the relationship between the performance of ADHD patients under stress conditions and GC response, finding that increased salivary GC levels were negatively correlated with aggressive behavior in ADHD patients, while in patients with decreased GC levels after stress, the absolute value of the decrease was negatively correlated with attention levels, indicating that GC levels are closely related to attention deficits, hyperactivity, and impulsive behavior.
Conduct disorder (CD) is a common comorbidity of ADHD, and studies related to CD have found that CD symptoms are negatively correlated with salivary GC levels, with a higher correlation with aggressive CD symptoms than with other symptoms. Northover et al.［34］ found that ADHD patients with comorbid CD exhibited low GC responses, and Shoal et al.［35］ found in longitudinal studies that low salivary GC levels at ages 10-12 were significantly correlated with low harm avoidance and self-control and high aggression at ages 15-17, suggesting that GC dysregulation affects the severity of symptoms in ADHD patients. Similar to ADHD patients, studies related to post-traumatic stress disorder have also found that patients have lower baseline levels of GC in their blood. Spencer et al.［36］ showed a bidirectional correlation between ADHD and post-traumatic stress disorder, although the underlying mechanisms have yet to be elucidated.
The feedback regulation process of GC is regulated by both mineralocorticoid receptors (MR) and GR. These two receptors play important roles by affecting the negative feedback of GC in the HPA axis. In psychiatric disorders, the mediating effects of MR and GR are quite significant, as these receptors are related to the regulation of systems associated with memory, behavioral responses, fear, and anxiety. MR is an important inhibitory control factor of the HPA axis, and under stress conditions, GR gradually replaces MR to bind with GC. Blocking MR and GR can lead to anxiety and panic responses, while MR antagonists can enhance feelings of fear. Such studies indicate that changes in MR and GR can affect behavioral and emotional changes in neuropsychiatric disorders［37］. Thus, abnormalities in MR, GR, and GC may play an important role in the pathogenesis of ADHD, particularly in behavioral and emotional changes.
4 Interaction Between Monoamine Neurotransmitters and the HPA Axis
Under stress experimental conditions, F344 rats exhibit ADHD-like behaviors and elevated GC levels, accompanied by increased mRNA expression of hypothalamic corticotropin-releasing factor, decreased mRNA expression of hippocampal GR, and reduced dopamine turnover rates in the prefrontal cortex, striatum, and hippocampus［38］. Rats exposed to prenatal GC also exhibit persistent dysregulation of tryptophan hydroxylase expression into adulthood［39］. This suggests that GC can influence monoamine neurotransmitters such as 5-HT and dopamine through various pathways. Animal experiments have shown that long-term exposure to dexamethasone can lead to dose-dependent increases in MAOA and MAOB activity in the prefrontal cortex and increased 5-HT turnover rates［40］. Studies suggest that GC use can increase MAOA levels, thereby affecting monoamine neurotransmitters［41］.
Chen et al.［42］ also found that drugs that act by inhibiting presynaptic DAT and increasing dopamine/NE concentrations in the synaptic cleft—methylphenidate and atomoxetine—can increase plasma GC levels in ADHD patients or animal models. At the same time, GC may elevate monoamine neurotransmitter levels and improve ADHD symptoms through various pathways affecting GR and DAT functions. The above studies suggest that there may be an interaction between the levels of dopamine/NE in the central nervous system and the HPA axis.
5 The Role of KLF11 in Mediating the Interaction Between HPA Axis and MAOA Function
MAOA can be regulated by GC through various pathways. GC binds to GR in the cytoplasm to form a GC-GR complex, which enters the nucleus and binds to GC response elements in the MAOA promoter to promote MAOA expression. Additionally, there are SP binding sites in the MAOA promoter region that can bind to members of the Sp1 Kruppel-like transcription factor family to regulate the expression of downstream genes［41］. The KLF family is a widely present class of basic transcription element-binding proteins in eukaryotes, acting as versatile transcription factors involved in regulating various cell proliferation, differentiation, and tissue development processes［43］. Among them, the expression of KLF9, KLF11, KLF15, SP1, etc., can be upregulated by GC. Bagamasbad et al.［44］ identified several GC response elements in the KLF9 gene sequence, suggesting that some members of the Sp1 Kruppel-like transcription factor family are direct response genes to GC, with the expression of KLF11 and SP1 positively correlated with MAOA［41,45］.
Numerous studies have shown that the expression of KLF11 can enhance the catabolism of monoamine neurotransmitters, possibly through promoting MAO pathways［46］. Research indicates that KLF11 can promote the TGF-β signaling pathway by transcriptionally inhibiting Smad7, while TGF-β affects the differentiation and maintenance of dopaminergic neurons. In one study, Harris et al.［47］ found that the expression of KLF11 in the prefrontal cortex of patients with depression increased by 36% compared to the control group and was positively correlated with MAOA expression. This suggests that KLF11 may be a key interaction point in the regulation of monoamine neurotransmitter levels by the HPA axis and MAOA.
6 Conclusion and Outlook
Given that abnormal expression of MAO leads to enhanced catabolism of monoamine neurotransmitters, resulting in disrupted dopamine/NE balance, which is associated with impulsive and aggressive behaviors, it is an important mechanism in the pathogenesis of ADHD. At the same time, abnormal GC responses and dysfunction of the HPA axis are significant features of ADHD. Exploring the interaction between MAO and the HPA axis will help further reveal the possible pathogenesis of ADHD.
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