Role of adenosine in the pathophysiology and treatment of attention deficit hyperactivity disorder

Abstract

Attention deficit hyperactivity disorder (ADHD) is a complex neurodevelopmental condition characterized by persistent inattention, hyperactivity, and impulsivity. Although its precise etiology remains unclear, current evidence suggests that dysregulation within the neurotransmitter system plays a key role in the pathogenesis of ADHD. Adenosine, an endogenous nucleoside widely distributed throughout the body, modulates various physiological processes, including neurotransmitter release, sleep regulation, and cognitive functions through its receptors. This review critically examines the role of the adenosine system in ADHD, focusing on the links between adenosine receptor function and ADHD-related symptoms. Additionally, it explores how adenosine interacts with dopamine and other neurotransmitter pathways, shedding light on its involvement in ADHD pathophysiology. This review aims to provide insights into the potential therapeutic implications of targeting the adenosine system for ADHD management.

Introduction

Cell signaling pathways are an important area of study in epidemiology, offering valuable insights into the mechanisms underlying various diseases. Among these pathways, adenosine signaling holds particular significance due to its involvement in key physiological processes, including immune response, tissue repair, and energy metabolism. Dysregulation of this pathway has been implicated in a wide range of pathological conditions, spanning cardiovascular diseases to neurodegenerative disorders. Identifying population-specific variations in adenosine signaling can enhance our understanding of disease susceptibility, progression, and therapeutic response, providing a foundation for the development of targeted prevention and intervention strategies tailored to high-risk groups. Emerging evidence suggests that attention deficit hyperactivity disorder (ADHD) may also be linked to alterations in the adenosine signaling pathway, warranting further investigation.

ADHD is the most prevalent neurodevelopmental disorder in children, affecting approximately 5% of the global population [1]. Individuals with ADHD exhibit a range of symptoms, including hyperactivity, inattention, impulsivity, and difficulties in social interaction and academic performance. The neurobiological underpinnings of ADHD are complex, involving dysfunction across multiple brain regions and neurotransmitter systems. These include neurotransmitter imbalances, structural and functional brain abnormalities, altered neural network connectivity, genetic predispositions, and environmental factors. One of the most widely accepted neurobiological models of ADHD focuses on the dysregulation of dopamine and norepinephrine. Dopamine, a critical neurotransmitter in the brain, modulates reward processing, motivation, attention, and motor control, primarily through neural signaling in the striatum [2] and prefrontal cortex [3]. It also plays a role in motor control and reward learning [4] with precise temporal dynamics. Norepinephrine is also integral to attention, stress response, and emotional regulation.

Variations in the adenosine signaling pathway across populations have been linked to an increased incidence of certain diseases, thus providing the basis for the development of prevention or treatment strategies targeting these pathways.

Clinical evidence of dysfunctional adenosine signaling pathway in ADHD

Emerging clinical evidence has increasingly highlighted the role of a dysfunctional adenosine signaling pathway in the pathophysiology of ADHD. One notable study, the Swedish Child and Adolescent Twin Study (CATSS), identified several single nucleotide polymorphisms (SNPs) within the ADORA2A gene, such as rs35320474, as significantly associated with ADHD traits [5]. Importantly, this association remained robust even after stringent corrections for multiple comparisons, underscoring the potential involvement of ADORA2A in the manifestation of ADHD characteristics. Similarly, a study of Korean children diagnosed with ADHD identified significant associations between ADHD prevalence and polymorphisms in adenosine A2A receptor genes, reporting that the rs5751876 TC genotype at the ADORA2A locus may be linked to a reduced risk of ADHD. Individuals with this genotype exhibited a lower likelihood of developing ADHD compared to those with other genotypes, such as TT or rs2298383 CC [6]. The consistency of these findings across diverse populations and regions suggests that adenosine receptor polymorphisms may play a crucial role in the manifestation of ADHD characteristics.

Mechanisms of adenosine signaling in ADHD pathogenesis

Interactions between adenosine and dopamine in the brain

Adenosine and dopamine interact within specific brain regions through their respective receptors and signaling pathways. Research has shown that individuals with ADHD exhibit lower dopamine receptor density in certain brain regions compared to those without the disorder [7], suggesting a reduced capacity for dopamine to exert its effects, which may contribute to the core symptoms of ADHD. Dopamine signaling is mediated through two primary receptor types: D1 receptors, which are typically associated with stimulatory effects, and D2 receptors, which are generally associated with inhibitory effects. Adenosine, an endogenous neuromodulator known for its sleep-inducing properties, interacts with A1 and A2A receptors. A2A receptors play a dominant role in promoting sleep, while A1 receptors exhibit regional specificity across different brain regions [8] and are primarily associated with inhibitory signal transduction pathways. When adenosine binds to the A1 receptor, it reduces the production of cyclic adenosine monophosphate (cAMP), which, in turn, decreases the activity of protein kinase A (PKA) [9]. This cascade ultimately suppresses signaling through dopamine D1 receptors, leading to a reduction in dopaminergic signaling (Fig. 1). This mechanistic pathway potentially underlies the neurobiological deficits in dopaminergic signaling that are commonly observed in ADHD patients.

Fig. 1.

Adenosine exerts an antagonistic interaction with dopamine D1 receptors through its A1 receptors

In contrast to A1 receptors, adenosine A2A receptors are primarily associated with excitatory signal transduction pathways. When adenosine binds to the A2A receptor, it triggers an increase in cAMP levels and enhances the activity of PKA. This signaling cascade promotes the release of dopamine, highlighting the significant role of A2A receptors in modulating dopaminergic transmission [9].

The interaction between dopamine and adenosine is particularly prominent in striatal neurons, where their receptors (D1 and A2A) jointly regulate PKA activity. This interplay is essential for maintaining proper striatal function and motor control. Dopamine, through its D1 receptors, activates PKA in direct pathway striatal projection neurons (dSPNs), which are critical for facilitating movement. At the same time, indirect pathway striatal projection neurons (iSPNs) experience a greater increase in PKA activity during movement, primarily mediated by A2A receptors [9]. In summary, while dopamine activates PKA via D1 receptors in dSPNs, adenosine primarily drives the increase in PKA activity in iSPNs via A2A receptors.

Adenosine A2B receptors exhibit an antagonistic relationship with dopamine D2 receptors (Fig. 1). Experiments have observed that when agonists targeting the A2B receptors are introduced, there is an observed increase in the release of catecholamines from the carotid body. Conversely, the application of A2B receptor antagonists reduces the release of catecholamines. Notably, dopamine D2 receptor agonists and antagonists demonstrate opposing effects on catecholamine release [10, 11]. This pharmacological evidence, derived from studies on rat cerebrospinal fluid, highlights the antagonistic interaction between adenosine A2B and dopamine D2 receptors. The role of A2B receptors in modulating catecholamine release, particularly in relation to dopamine D2 receptor activity, suggests a potential mechanism through which A2B receptors may influence ADHD symptoms. This interaction points to a broader regulatory network in which adenosine and dopamine pathways intersect, contributing to the neurochemical imbalances observed in ADHD.

Adenosine and norepinephrine

Abnormal elevations in norepinephrine levels have been observed in specific brain regions of individuals with ADHD. The mechanisms underlying these changes are complex, and adenosine receptors play a crucial role in modulating the release of norepinephrine. Research suggests that adenosine receptors, particularly the A1 subtype, inhibit norepinephrine release in certain neural circuits. For example, studies of rabbit hippocampal slices have demonstrated that the electrical stimulation-induced overflow of [3H]-norepinephrine is inhibited by both α2-autoreceptors and adenosine A1 receptors [12], suggesting that adenosine may suppress norepinephrine activity. Further experiments using electrical stimulation of rat cortical slices found that both adenosine triphosphate (ATP) and adenosine diphosphate (ADP) inhibit the release of norepinephrine within a certain range [11]. Additionally, uridine 5’-diphosphate (UDP) can inhibit the release of norepinephrine through activation of the P2Y6 receptor, an effect that can be blocked by P2Y6 receptor antagonists. Once ATP is metabolized into ADP and adenosine, selective agonists for the A1 and A2A receptors (CPA and CGS21680) can inhibit norepinephrine release induced by N-methyl-D-aspartate (NMDA) [13].

Adenosine modulates neuronal sensitivity to acetylcholine

Acetylcholine (ACh) plays a vital role in regulating cognitive functions such as attention, which may indirectly influence symptom manifestation in individuals with ADHD. An important physiological function of ACh is to inhibit high-frequency ripple rhythms in the hippocampus during wakefulness and rapid eye movement sleep, ensuring that the theta rhythm—essential for “online” learning and memory encoding processes—can dominate [14]. Children with ADHD often exhibit disruption in the regulatory function of ACh, potentially contributing to their observed difficulties in learning and memory, as well as deficits in executive functions, including difficulties in planning, organizing, initiating tasks, and self-regulation [15]. ACh is heavily involved in these cognitive processes, and its dysregulation may exacerbate impairments in executive functioning. Notably, during aversive learning, ACh levels increase in certain brain regions, such as the striatum and nucleus accumbens [16], highlighting its potential role in modulating cognitive control and contributing to challenges in executive functioning, which consequently affect learning and memory capabilities.

Adenosine A1 and A2A receptors are known to influence the release of ACh [17]. ACh influences intracellular signaling pathways via its receptors, including nicotinic and muscarinic ACh receptors (nAChRs and mAChRs, respectively), while adenosine modulates neuronal excitability through its G protein-coupled receptors, such as A1 and A2A. Activation of these receptors can alter intracellular second messengers, thereby affecting nerve cell function [18]. ACh is typically associated with promoting arousal and attention, whereas adenosine is linked to inhibitory signaling and sleep modulation, particularly through its actions in the prefrontal cortex and pontine reticular formation—regions integral to the regulation of sleep and wakefulness. Research has demonstrated that microinjection of adenosine A1 receptor antagonists, as well as microdialysis delivery of adenosine receptor agonists and antagonists into the prefrontal cortex, significantly alters ACh release in the pontine reticular formation [19]. Under certain conditions, adenosine can reduce the release of ACh in hippocampal and cortical synaptosomes via A1 receptors, an effect that can be antagonized by caffeine. However, A2A receptor activation increases ACh release in the hippocampus, without affecting its release in the striatum or the release of catecholamines [20]. Thus, adenosine A1 receptors regulate ACh release in the striatum and hippocampus, while adenosine A2A receptors primarily influence ACh release in the hippocampus.

Adenosine and gamma-aminobutyric acid (GABA)

GABA, a crucial inhibitory neurotransmitter, plays a key role in modulating neuronal excitability and is implicated in various physiological functions, including anxiety reduction, sleep promotion, and muscle tone regulation. Although the involvement of GABA in ADHD is not as extensively studied as that of dopamine and norepinephrine, evidence suggests that it may exert indirect effects on the disorder.

Adenosine, acting through A1 and high-affinity A2A receptors, influences GABA release in the brain. Selective activation of these receptors has been shown to inhibit GABA release in the cerebral cortex of ischemic rats [21]. Studies have also demonstrated that A2A receptors regulate GABA release by modulating cAMP production and PKA activity, a process also involving histamine H3 receptors (H3Rs) [22]. Research has also reported that A2A receptors function as sensors of active GABAergic synapses, controlling the stability of these synapses by regulating the release of GABA, ATP, and adenosine [23]. This regulatory role emphasizes the importance of A2A receptors in neural circuit formation, with potential implications for the neurological dysfunction observed in ADHD.

Serotonin (5-HT) and adenosine

ADHD is often accompanied by emotional disturbances, including anxiety and mood disorders [24, 25]. 5-HT plays a key role in regulating mood, as well as various other physiological functions [26, 27]. Recent research has suggested that the activation or blockade of adenosine receptors can significantly influence 5-HT release, which may explain the effects of substances such as caffeine and 3,4-methylenedioxymethamphetamine (MDMA) on the nervous system. Caffeine, by blocking adenosine A1 and A2A receptors, has been shown to exacerbate the effects of MDMA on the release of dopamine and 5-HT, and may also enhance MDMA toxicity [28]. This evidence points to the possibility that adenosine receptor activity, whether through activation or blockade, modulates serotonin release and highlights a potential mechanism by which caffeine and MDMA affect neurotransmitter dynamics. Subsequent research has also demonstrated that regular physical exercise can mitigate anxiety-like behaviors in mice treated with a selective 5-HT2A receptor antagonist (MDL11930), reducing PKA activation mediated by adenosine A2A receptors through a mechanism dependent on 5-HT2A receptor signaling in the basolateral amygdala (BLA) [29]. These findings indicate that 5-HT2A receptors in the BLA can inhibit the function of A2A receptors. Additionally, the rapid and transient modulation of neurotransmitters such as 5-HT by adenosine may have significant therapeutic implications, particularly for conditions such as depression, ADHD, and neurological injuries [30]. Understanding the interaction between adenosine and 5-HT, as well as their underlying mechanisms, is essential for the development of novel therapeutic strategies targeting ADHD and related emotional disorders.

Role of adenosine signaling dysfunction in ADHD

Effects on attention

Adenosine plays a significant role in regulating attention, primarily through its impact on the sleep–wake cycle. Adenosine influences attention and executive function by modulating the expression of A1 receptors in critical brain regions involved in these processes (Fig. 2). Sleep deprivation, a common issue in individuals with ADHD, has been shown to increase the expression of adenosine A1 receptors in the prefrontal cortex [31], which may lead to impairments in attention and executive functions. Adenosine also reduces high-frequency oscillations during wakefulness by inhibiting cholinergic neurons in the basal forebrain—neurons that are crucial for maintaining arousal and attention [32]. These oscillations are essential for normal cognitive and attentional functions, and adenosine-mediated inhibition of cholinergic neurons, through the activation of A1 receptors [33], may lead to attention deficiencies. Thus, the inhibitory effects of adenosine on cholinergic activity can contribute to attention impairments in individuals with ADHD. Increased adenosine levels are associated with greater sleep pressure, leading to reduced alertness and cognitive function. Individuals with ADHD frequently experience sleep disturbances, such as delayed sleep onset, frequent nighttime awakenings, and poor sleep quality [34]. These sleep issues may further disrupt the normal regulation of adenosine, exacerbating deficits in alertness and attention.

Fig. 2.

Adenosine plays a key role in regulating attention and executive functions by affecting the sleep-wake cycle and the expression of A1 receptors in the brain's relevant regions. Sleep deprivation can disrupt its normal regulation, leading to attention deficits in individuals with ADHD

As a neuromodulator, adenosine regulates various aspects of the sleep–wake cycle and attention. As wakefulness extends, adenosine levels rise, promoting sleep and diminishing alertness by binding with A1 receptors. This regulatory process is crucial for the prefrontal cortex, a region responsible for executive functions, including the regulation of attention and planning. Sleep deprivation disrupts this balance, altering adenosine receptor expression and impairing attention and executive functions. Adenosine A2B receptors are also key participants in neuron-astrocyte communication, essential for maintaining synaptic plasticity, crucial for learning and memory. Studies have found that the absence of A2B receptors in astrocytes leads to recognition memory impairment and sleep disruption [35]. Furthermore, adenosine inhibits cholinergic neurons, reducing high-frequency oscillations essential for normal cognitive functions during wakefulness. Common sleep disturbances in ADHD patients, such as poor sleep quality and delayed onset, may further decrease alertness and attention by affecting the regulatory mechanisms of adenosine. Therefore, a thorough understanding of the mechanisms involved may contribute to the development of new therapeutic strategies for ADHD, particularly by targeting sleep improvement and sleep–wake cycle regulation.

Hyperactivity and impulsive behavior

Adenosine plays a pivotal role in modulating the sleep–wake cycle and may influence the hyperactivity and impulsive behaviors frequently observed in patients with ADHD. Changes in adenosine levels or receptor sensitivity may potentially impact dopaminergic activity, which, in turn, may affect the behavioral manifestations associated with ADHD. In regions such as the prefrontal cortex and anterior cingulate cortex, adenosine, particularly through its A2A receptor, may modulate motor control and dopaminergic signaling, thus affecting hyperactivity, impulsivity, and sensitivity (Fig. 2). A2A receptors are predominantly expressed in iSPNs and form heterodimers with dopamine D2 receptors. Activation of these receptors can increase the excitability of iSPNs and affect the function of D2 receptors through allosteric modulation in the heterodimer [36]. This interaction is critical for maintaining the balance between excitatory and inhibitory signaling in the brain, which plays a key role in motor control and decision-making processes. The antagonistic relationship between A2A and D2 receptors occurs not only in the dorsal striatum, which governs motor activity (located at postsynaptic positions on dendrites and dendritic spines), but also in the nucleus accumbens (ventral striatum), which affects goal-directed behaviors [36, 37]. However, more research is needed to clarify the mechanisms by which adenosine affects activity levels in individuals with ADHD. The nucleus accumbens, a core component of the reward system of the brain, is particularly relevant to the motivational deficits seen in ADHD. Disruptions in this region can impair reward anticipation and pursuit, leading to heightened impulsivity and difficulty in delayed gratification often observed in individuals with ADHD. Fluctuations in dopamine levels, which are modulated by adenosine through its A1, A2A, and A2B receptors, directly affect reward processing and risk-taking behaviors. These dopaminergic changes, mediated by adenosine, influence key behaviors via projections to different pathways in the brain, including nigrostriatal, mesolimbic, and prefrontal cortical circuits.

Cognitive difficulties

Cognitive functions such as attention and memory are key components of the brain’s cognitive architecture. Adenosine, through its interactions with various receptors, plays a significant role in modulating these functions. Inattention, a core symptom of ADHD [38], may be linked to dysfunction in brain areas involved in cognitive control. Disruptions in adenosine signaling may influence these regions and, consequently, cognitive performance. In particular, the inhibition of adenosine A2B receptor activity has been shown to enhance dopaminergic signaling [10], potentially improving cognitive functions, such as attention and working memory. Key brain regions, such as the striatum and prefrontal cortex, which are involved in cognitive control, interact with adenosine and its receptors, modulating critical cognitive functions such as memory and attention. Regulation of the adenosine system, especially the inhibition of A2B receptors, may indirectly bolster attention and working memory by facilitating dopaminergic signaling within these regions (Fig. 2).

As a key neuromodulator, adenosine regulates neural activity by activating or inhibiting different receptors, including A1 and A2 receptors, which influence the transmission of nerve impulses and the function of neural networks. This regulatory role extended to the sleep–wake cycle, with direct implications for cognitive functions, particularly in areas related to attention and memory. In individuals with ADHD, adenosine-mediated improvements in dopamine signaling via A2A receptors may help enhance cognitive performance. Furthermore, adenosine has also been shown to protect neurons and promote cognitive health by modulating neuroplasticity [39] and exerting anti-inflammatory effects [40]. Thus, adenosine plays a multifaceted role in regulating cognitive functions in the brain, providing a valuable perspective for understanding cognitive functions and their role in neurodevelopmental disorders, such as ADHD, and for developing new therapeutic approaches.

Emotional disorders

In addition to the core symptoms of inattention and hyperactivity-impulsivity, children with ADHD may also experience a wide range of emotional challenges, including difficulties in emotional regulation, irritability, mood swings, anxiety, depression, social difficulties, oppositional defiant disorder (ODD), and low self-esteem. Addressing these issues requires professional intervention, along with support from both family and educational environments, to help these children better manage their emotions, improve social skills, and build a healthy sense of self-worth.

The serotonergic system, originating from the median and dorsal raphe nuclei, is deeply involved in impulse control, emotional regulation, and decision-making processes. Adenosine A2A receptor agonists have been shown to enhance the release of 5-HT, which plays a central role in maintaining emotional stability and reducing anxiety and depression [27]. Disruptions in the 5-HT system are associated with a range of emotional disorders, including depression and anxiety, which are commonly co-morbid with ADHD. Consequently, the activity of adenosine A2A receptors may be linked to emotional disorders in ADHD patients, as agonists of these receptors can increase 5-HT levels in brain regions involved in impulse control and emotional regulation (Fig. 2).

Adenosine receptors, particularly the A1 and A2A subtypes, contribute considerably to the regulation of emotional states in individuals with ADHD by finely tuning neurotransmission and participating in various biological processes related to stress and emotional control. Activation of A1 receptors is associated with reductions in anxiety, promotion of sleep, and alleviation of stress, while activation of A2A receptors is associated with increased arousal and anxiety, potentially exacerbating feelings of unease [41]. The distinct roles of these two receptors in emotional states and stress response highlight the complexity of the adenosine system in regulating anxiety and sleep.

Potential of adenosine system in ADHD treatment

Current pharmacological treatments for ADHD encompass both stimulant medications, such as methylphenidate and amphetamines, and non-stimulant medications, such as atomoxetine, offering short-term efficacy and generally favorable tolerability [42]. As a central nervous system stimulant, methylphenidate enhances neurotransmitter concentrations in the brain by inhibiting dopamine and norepinephrine reuptake, thereby improving focus, reducing impulsivity, and regulating hyperactivity [43, 44]. Similarly, amphetamines elevate dopamine and norepinephrine levels in the brain by both inhibiting their reuptake and facilitating their release, thereby enhancing the functionality of the prefrontal cortex, a key region associated with executive function, attention, and behavioral control [45]. These stimulants, particularly amphetamines, are widely recognized as the primary therapeutic approach in adult ADHD patients [42]. In contrast, atomoxetine, a selective norepinephrine reuptake inhibitor (NRI), primarily increases norepinephrine levels [46], with minimal impact on dopamine. As a non-stimulant, atomoxetine may be a safer alternative for patients at risk of substance abuse or dependence compared to other ADHD medications. Despite their effectiveness, long-term use of ADHD medications such as methylphenidate, amphetamine, and atomoxetine can lead to the development of tolerance. Over time, patients may require progressively higher doses to achieve the same therapeutic outcomes, posing challenges for sustained treatment efficacy.

As a widely used stimulant, caffeine exerts significant excitatory effects on the central nervous system by competitively binding to adenosine receptors, especially A1 and A2A, with this antagonistic effect reducing the inhibitory impact of adenosine on neural transmission. Notably, caffeine and other adenosine receptor antagonists have been shown to alleviate symptoms of ADHD [47], affecting attention, alertness, and anxiety [47–49]. Acute caffeine pretreatment has been found to block the effects of cannabinoid agonists, while chronic caffeine consumption can increase impulsive behavior and enhance the effects of cannabinoids. This dual effect, and its impact on impulsivity, is dependent on the context and duration of exposure [50]. Studies have shown that caffeine intake, through its interactions with A2A receptors, can rescue neuronal development in vitro in frontal cortical neurons in a rat model of ADHD. Spontaneously hypertensive rats, commonly used to model ADHD, exhibit abnormalities in both dopamine and adenosine neurotransmission, which may have significant implications for ADHD pathology [49]. Caffeine, as an antagonist of A1 and A2A receptors, can impact synaptic plasticity, a key process in learning and memory formation. In normal neurotransmission, dopamine D2 receptors are associated with behavioral regulation and reward system signaling. When adenosine binds to its receptors, it typically suppresses D2 receptor activity, leading to reduced dopamine signaling efficiency. However, by blocking adenosine receptors, caffeine mitigates this inhibitory effect, thereby enhancing dopaminergic transmission. This mechanism may help alleviate behavioral symptoms related to ADHD by increasing dopamine signaling, thereby improving cognitive and behavioral functions. In spontaneously hypertensive rats, caffeine intake during adolescence, combined with exercise, has been shown to increase SNAP-25, syntaxin, and 5-HT levels in the hippocampus and prefrontal cortex, as well as dopamine levels in the striatum. Interestingly, caffeine may exhibit sex-specific effects on ADHD symptoms, particularly improving cognitive impairments in females [51]. Moreover, early caffeine consumption, beginning in childhood, may help regulate both behavioral and neurobiological changes associated with ADHD.

In summary, caffeine can alleviate ADHD symptoms by enhancing cognitive and behavioral performance through its antagonistic effects on adenosine receptors, thereby increasing dopaminergic activity and regulating 5-HT levels. These findings highlight the potential of targeting adenosine signaling as a therapeutic strategy for managing ADHD.

Conclusions

As a crucial regulator of energy balance, adenosine exerts its influence on the function of various organs through its distinct signaling pathways [52]. Targeted modulation of specific adenosine receptor subtypes or enzymes involved in its metabolic pathways offers promising therapeutic strategies for conditions such as ADHD. The neurobiological mechanisms of ADHD are highly complex, involving multiple neurotransmitter systems, with adenosine signaling emerging as an essential player in the regulation of dopamine, norepinephrine, ACh, GABA, and 5-HT. These interactions may provide valuable insights into alleviating ADHD symptoms. Clinical studies linking adenosine receptor polymorphisms to ADHD symptoms, along with evidence of the influence of adenosine on key neurotransmitters, underscore its multifaceted role in the pathophysiology of the disorder. Caffeine and other adenosine receptor antagonists have demonstrated potential in improving cognitive and behavioral symptoms by modulating dopaminergic activity, suggesting that targeted manipulation of adenosine signaling could be a promising avenue for the development of new therapeutic strategies. However, the heterogeneity of ADHD and varying responses to treatment necessitate consideration of individual differences in adenosine signaling and call for personalized therapeutic approaches. Further research is needed to elucidate the precise mechanisms by which adenosine receptor activation or inhibition affects ADHD-related neurobiology. A deeper understanding of these mechanisms could facilitate the development of targeted pharmacological interventions that fine-tune adenosine pathways, offering new hope for individuals with ADHD. In conclusion, modulation of the adenosine system represents a promising frontier for effective and personalized ADHD treatments, emphasizing the need for continued investigation into its neurobiological significance and therapeutic potential.

Author contributions

Qingxia Jia: Writing–original draft. Hongwan Tan: Writing–review & editing. Tingsong Li: Writing–review & editing. Xiaoling Duan:Conceptualization, Writing–review & editing. All authors reviewed the manuscript.

Funding

This work was supported by the Science-Health Joint Medical Scientific Research Project of Chongqing (No. 2023MSXM144) and the Youth Basic Research Project from the Ministry of Education Key Laboratory of Child Development and Disorders (YBRP-2021XX).

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval

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Consent to participate

Not applicable.

Competing interests

The authors declare no competing interests.