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Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by a persistent pattern of inattention and/or hyperactivity-impulsivity. ADHD impairments arise from irregularities primarily in dopamine (DA) and norepinephrine (NE) circuits within the prefrontal cortex.
- attention deficit hyperactivity disorder
- impulsivity
- ADHD
1. Introduction
Attention Deficit Hyperactivity Disorder (ADHD) is the most commonly diagnosed and treated mental disorder during childhood [1] and it is increasingly diagnosed and treated in during adulthood [2]. ADHD is a neurodevelopmental disorder characterized by a pattern of inattention and/or hyperactivity-impulsivity, persisting no less than six months, that is inconsistent with developmental level and has negative impact in at least two settings (academic, occupational or social) [3]. Inattention refers to important difficulties in sustaining attention to tasks that do not deliver a high level of stimulation or regular rewards, distractibility, and difficulties with organisation. Hyperactivity refers to disproportionate motor activity and difficulties with remaining still, most manifest in structured situations that involve behavioral self-control. Finally, impulsivity is a propensity to behave in response to immediate stimuli, without consideration of the risks and consequences [4]. Specific manifestations vary across individuals, and may change over the course of development. Depending on the symptoms presented, three different types of ADHD can be diagnosed: predominantly inattentive presentation, predominantly hyperactive-impulsive presentation, or combined presentation [3,4]. Although ADHD onset occurs during childhood and it often persists into adulthood, there is an important knowledge gap concerning ADHD lifespan aspects [5]. Population surveys suggest that ADHD occurs in most cultures in about 5% of children and about 2.5% of adults [6] and, as of 2019, it was estimated to affect 84.7 million people worldwide [7]. ADHD management recommendations depend on the country [8,9,10] and usually include psychotherapy (essentially Cognitive Behavior Therapy, CBT), lifestyle changes and medications [11]. ADHD medication treatment, however, has been historically considered controversial [12], particularly due to its side effects [13,14,15]. In the face of these controversies and high rates of diagnosis, alternative/complementary pharmacological therapeutic approaches for ADHD are needed.
Although larger ADHD models containing supplementary pathways have been suggested [16,17], it is widely accepted that ADHD impairments, including selective and sustained attention, impulsivity, and motor activity, arise from abnormalities in different circuits involving the prefrontal cortex [18]: sustained attention is modulated by a cortico-striato-thalamocortical (CSTC) loop that comprises the dorsolateral prefrontal cortex (DLPFC) projecting to the striatal complex. Selective attention is modulated by a cortico-striato-thalamo-cortical (CSTC) loop ascending from the dorsal anterior cingulate cortex (dACC) and projecting to the striatal complex, followed by the thalamus, and back to the dACC. Impulsivity is related to a cortico-striato-thalamocortical (CSTC) loop that contains the orbitofrontal cortex (OFC), the striatal complex, and the thalamus. Finally, motor activity, including hyperactivity and psychomotor agitation or retardation, can be modulated by a cortico-striato-thalamo-cortical (CSTC) loop arising from the prefrontal motor cortex to the lateral striatum to the thalamus and back to the prefrontal motor cortex. ADHD patients cannot activate prefrontal cortex areas in an appropriate manner when responding to cognitive tasks requiring attention and executive control, and show a dysfunction in reward and motivation, hindering cognitive control of behaviour [19,20]. Children diagnosed with ADHD, in this regard, need stronger incentives to adapt their behaviour [21], showing impaired responses to partial schedules of reinforcement and difficulties in delaying gratification [22,23].
In ADHD, inefficient information processing and arousal-related behaviours are hypothetically caused by imbalances mainly in the dopamine (DA) and norepinephrine (NE) circuits [24,25] and the serotonin (5-HT), glutamate (GLU), and acetylcholine (ACh) pathways within these areas of the brain [26,27,28].
2. Researches and findings
ADHD is characterized by symptoms including attention deficits, impulsivity, and hyperactivity [3,4] that frequently persist throughout life [1,2,6]. Prefrontal cortex function modulation and attentional/behavioral regulation depends on the optimal release of signalling molecules such as NE, DA [24,25], as well as 5-HT, GLU, or ACh [26,27,28]. In this respect, genes, including the DAT or the DRD4 [31,32] or the SERT, the SNAP-25, and the BDNF [29,30], might play a role in causing ADHD. Therefore, agents that can lead to the optimal balance of these organic compounds are hypothetically beneficial in patients with ADHD by mainly returning prefrontal activity to adequate functional levels [18,33]. In this sense, it has long been discussed whether caffeine could become an effective pharmacological compound for the management of symptoms of ADHD [64,65].
Regarding attention, caffeine treatment improved the attentional and behavioral flexibility of SHRs [51], the spatial attention of 6-OHDA lesioned rats [53], and SI in ICR mice [52] during adolescence. Caffeine treatment improved the reaction time of LE and CD rats [55] and focus and attention in zebrafish [54] during adulthood.
Regarding learning and memory, caffeine treatment plus physical exercise during adulthood and adolescence improved working memory in SHRs [56]. In the same vein, caffeine treatment alone restored non-associative learning in female SHRs [57], improved working memory in SHRs [59], female SHRs [62], and adolescent SHRs [57]. The administration of caffeine improved spatial learning deficit in SHRs, increased memory retention in WKY rats [60], and improved spatial short-term memory in SHRs [51] and female SHRs [57].
Concerning olfactory discrimination, caffeine treatment, together with physical exercise, was able to restore olfactory discrimination in SHRs during adolescence or adulthood [56]. Concerning blood pressure, caffeine treatment did not alter the hypertensive phenotype in SHR [60,62] during adolescence or adult life [56], nor during the adult female SHR prepubertal period [59]. Finally, caffeine treatment did not alter body weight in SHRs [51,59].
Beyond its clear effects on improving performance in tasks requiring attention, learning, memory and olfactory discrimination, without altering blood pressure and body weight, the implication of caffeine in modulating ADHD-like hyperactivity symptoms remains controversial. Indeed, caffeine treatment plus physical exercise did not affect locomotor activity in SHRs [56]. In a similar manner, caffeine treatment alone did not alter locomotion in SHR [51,59,60], preadolescent SHR [57], or young LDLr mice [58]. Nonetheless, caffeine treatment did increase locomotor activity in adolescent female SHRs [57], zebrafish [54]. Furthermore, it produced an increase related to dose in locomotion in CD rats and a significant attenuation of CGS-21680-induced hypolocomotion in CD rats [55], and it attenuated locomotor activity in middle-aged LDLr mice [58] and 6-OHDA lesioned rats throughout the prepubertal period [53]. This apparent discrepancy may have resulted from caffeine ‘s promotion of different effects according to age and sex. In this regard, Nunes et al. [57] suggested that the intake of caffeine from the childhood period onwards may aggravate hyperactivity in females, if the consumption continues up to the adolescence period. Szczepanik et al. [58] linked the age-dependent effect induced by caffeine with the idea that the blockade of adenosine A1/A2A receptors attempts to renormalize a potentially maladaptive system [66], with age an important escalating factor in mice. In a different study, Ruiz-Oliveira et al. [54] proposed that caffeine-induced bursts of locomotion may be caused by a decrease in fatigue [67] rather than by an anxiogenic response. Importantly, the attenuation of motor activity by caffeine consumption was determined as a natural effect of growth rather than an effect of caffeine intake by Caballero et al. [53].
In terms of impulsivity, although acute pretreatment with caffeine increased the number of large-reward choices made by SHRs, chronic treatment with caffeine increased the impulsive phenotype and decreased choices of large rewards by SHRs [61]. This discrepancy may be explained by previous studies performed on animal models of brain diseases, showing that while acute treatment acts mainly on A1 receptors, chronic treatment acts mainly on A2A receptors [68]. Leffa et al. [61], in this direction, underscored the ability of the adenosine modulation system to control behavioral inhibition.
Besides reviewing animal studies deciphering the effects of caffeine in the modulation of ADHD-like symptoms, we reviewed for the first time animal studies examining the effects of caffeine and adenosine receptors on neurons isolated from SHRs, at the neuronal level.
In this respect, treatment with caffeine and physical exercise during the adolescence period augmented the quantity of SNAP-25, syntaxin, and serotonin in the prefrontal cortex and the hippocampus, as well as striatal dopamine quantity, in SHRs [56]. In a similar manner, caffeine treatment alone during the adolescence period attenuated the improvement in DAT density in the fronto-cortical and striatal terminals of SHRs and diminished the dopamine uptake by synaptosomes from SHRs’ fronto-cortical and striatal terminals [51]. Furthermore, Pandolfo et al. [51] demonstrated that fronto-cortical nerve terminals are provided with AdenosineA2A receptor, the target of chronic caffeine exposure, whose density was found to be increased in SHRs. Caffeine treatment normalized BDNF levels in the hippocampuses of SHR males, while the same treatment normalized TrkB receptors TrkB-FL and TrkB-T SHR in the hippocampuses of SHR females [57]. Finally, neurons from SHRs showed an inferior number of zero-branch points, and a superior number of two-branch-points-neurons following in vitro caffeine treatment consisting of 24 h of caffeine incubation. After treatment with caffeine, an increase in the total and maximal neurite length and a tendency toward a superior number of one-branch-point neurons was also observed for SHR neurons. The effect of caffeine on increasing maximal neurite length, and on recuperating the entire neurite length of neurons from SHR, was entirely blocked by PKA inhibitor. LY294002, as an inhibitor of PI3K, blocked caffeine’s effects on the increase in the amount of branch points in SHR neurons. Finally, the effect of caffeine on the prevention of reductions in the total neurite length, increasing maximal neurite length, and the number of roots was eradicated by the presence of PI3K inhibitor in SHR neurons [63].
This entry is adapted from the peer-reviewed paper 10.3390/nu14040739
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