Keywords

The incidence of attention-deficit/hyperactivity disorder (ADHD) is, very likely, increasingly diagnosed, from about 5 % of all children in the USA (Kalat 2001), to 5.1 million or 8.8 % of all children in the age-group 4–17 years (CDC 2011). The incidence over developmental trajectory breaks down as follows: (i) 6.8 % of all children aged 4–10 years (1 in every 14), (ii) 11.4 % of all children aged 11–14 years (1 in every 9), and (iii) 10.2% of all children aged 16–17 years (1 in every 10), with average age at current diagnosis 6.2, with “mild” ADHD diagnosed at 7 years, “moderate” at 6.1 years and “severe” at 4.4 years 3.5 million children taking medication. Boys (12.1 %) remain as more likely to be diagnosed than girls (5.5 %) to be diagnosed. High rates of comorbidity with of oppositional defiant disorder (ODD), anxiety, and depression in children with ADHD have been reported (Anckarsäter et al. 2006; Mitchison and Njardvik 2015; Garcia et al. 2013). The primary symptoms manifested in children with ADHD include: incessant talking in the classroom, restlessness, inattention, impulsiveness, lack of concentration, and hyperactivity (Antonini et al. 2015; Barkley et al. 2002; Bussing et al. 2015; Swanson et al. 1998). In adults with ADHD, symptom profiles are defined by poor attention with excessive distractibility, over-impulsivity, i.e., thoughtless utterances/actions, restlessness/hyperactivity, chronic procrastination, difficulty initiating and completing tasks, frequently losing objects, poor organization, planning and time management, and excessive forgetfulness (Froehlich et al. 2007, 2009, 2010, 2011; Jaber et al. 2015; Lin and Gau 2015; Micoulaud-Franchi et al. 2015). Individuals presenting ADHD exhibit excessive levels of default mode networkFootnote 1 activity during goal-directed tasks, which are associated with attentional disturbances and performance decrements. However, the process of downregulating the default mode network activity when preparing to switch from rest to task is unimpaired in adults with ADHD adults and these adults also lack switch-specific deficit in right anterior insula modulation (Sidlauskaite et al. 2015). In addition, individuals presenting ADHD show difficulties in upregulating the default mode network activity when switching from task phase to rest phase (Sidlauskaite et al. 2015). Kucyi et al. (2015) showed evidence of impaired cerebellar areas of the default mode network coupling with cortical networks in adult patients with ADHD and highlights a role of cerebro–cerebellar interactions in cognitive function. ADHD is associated with significantly increased mortality rates and individuals diagnosed with ADHD during adulthood show higher mortality rates than did those diagnosed in childhood and adolescence (Dalsgaard et al. 2015).

The vast number of studies examining neurobiological aspects of ADHD attests to variety of laboratory animal models available including (i) genetically based models, (ii) neurotoxin-induced models, (iii) Neonatal NMDA-R antagonist administration models, (iv) environmentally based models, and (v) sleep disorder problems. (i) Genetically based models present strains of rats/mice with particular, measureable ADHD phenotypes with phenotypic behaviors and biomarkers such as spontaneously hypertensive (SHR) rats, Naples high-excitability (NHE) rat, rats giving poor performers in the 5-choice serial reaction time task, dopamine transporter (DAT) knock-out mice, SNAP-25-deficient mutant coloboma mice, mice expressing a human mutant thyroid hormone receptor, nicotinic receptor knock-out mice, 22q11.2 deletion syndrome (Meechan et al. 2015), and tachykinin-1 receptor knock-out mice. (ii) Neurotoxin-induced models of ADHD applying N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) or 6-hydroxydopamine (6-OHDA) as catecholamine neurotoxins or 5,7-dihydroxytryptamine (5,7-DHT) to induce deficits. (iii) NMDA-R antagonist administration models administer MK-801, ketamine, ethanol, polychlorinated biphenyls, or phencyclidine (PCP). (iv) Environmentally based models such as pups reared in deprived environments or isolated housing or neonatal anoxia or variations of environmental stress (Ishii and Hashimoto-Torii 2015). (v) Complex regulatory circuits involving clock genes themselves and their influence on circadian rhythms of diverse body functions and behavioral domains form an important aspect of the gene-environment interaction (Dueck et al. 2015).

As indicated by Russell (2011), one major insight provided by animal models was the consistency of findings regarding the involvement of dopaminergic, noradrenergic, and sometimes also serotonergic systems, as well as glutamateric and GABAergic pathways (see also Russell 2007). Blockade of the N-methyl-d-aspartate receptors (NMDA-Rs) during the neonatal period has been to induce long-term behavioral and neurochemical alterations that are applied as laboratory models for ADHD, schizophrenia, borderline personality disorder and depression. During development, GABA exerts a depolarizing action on immature neurons. Ende et al. (2015) studied glutamate and GABA influences in relation to impulsiveness and aggressive behavior associated with the anterior cingulate cortex in the groups of female patients presenting borderline personality disorder and ADHD, respectively. The links between glutamate and GABA levels and further borderline personality disorder (symptom severity) and ADHD aspects (hyperactivity and inattention) were evaluated in an explorative manner. They acquired 1H MR spectra at 3T to determine the glutamate to total creatine ratios (Glu/tCr) and GABA levels from the anterior cingulate cortex in a borderline personality disorder group (n = 26), an ADHD group (n = 22), as well as a healthy control (HC) group (n = 30); all the participants were females. Both patient groups, i.e., borderline personality disorder and ADHD, presented higher scores on self-reported impulsiveness, anger, and aggression compared with the healthy controls. Anterior cingulate cortex GABA levels were significantly lower in ADHD than HC. Although measures of impulsiveness were related positively to glutamate and negatively to GABA, in the case of aggression only a negative correlation with GABA was obtained. This pattern of results may provide human in vivo evidence for the role of anterior cingulate cortex Glu/tCr and GABA in impulsiveness and aggression.

1 N-Methyl-d-Aspartate Receptors (NMDA-R) Linked ADHD Models

ADHD pathophysiology persists in an obscure manner with complex interactions between symptoms, staging, interventions, genes, and environments (Archer and Bright 2012; Archer and Kostrzewa 2012; Archer et al. 2011; Kyeong et al. 2015; Rommel et al. 2013; Schuch et al. 2015). Functional magnetic resonance imaging (fMRI) has shown that almost all test–retest reliability of resting state fMRI metrics presented significantly higher intra-class correlation coefficient in typically developing children than in with ADHD children for one or more brain regions studied (Somandepalli et al. 2015). Several physiological biomarkers besides brain neurochemical show deficits in the disorder: for example, serum levels of oxytocin in total subjects presenting ADHD were reduced significantly compared with those levels of neurotypical control individuals, and serum levels of oxytocin in drug naïve ADHD patients were significantly lower than those in medicated ADHD patients. Interestingly, there was a significant negative correlation between serum oxytocin levels and ADHD-RS total scores, as well as ADHD-RS inattentive scores in all ADHD patients Sasaki et al. 2015). The genetic factor in ADHD is undeniable (Fang et al. 2015; Salatino-Oliveira et al. 2015; Thapar and Cooper 2015; Van Rooij et al. 2015a; Pettersson et al. 2013), connected with sibling associations (Richards et al. 2015; Thissen et al. 2015; Van Rooij et al. 2015b), parents (Costa Dde et al. 2015; Grizenko et al. 2015; Van der Kolk et al. 2015), and with extremely high twin concordance (Arcos-Burgos et al. 2004; Ehli et al. 2012; Langner et al. 2013; McLoughlin et al. 2014; Garcia et al. 2014) and comorbidity (Volh et al. 2005; Garcia et al. 2013). The notion of an imbalance between central inhibitory/excitatory neurotransmitters is considered to exert an essential role in the pathophysiology of ADHD (Purkayastha et al. 2015; Sadile et al. 1996), although this is not always the case (Endres et al. 2015). For instance, in contrast to children, adult patients presenting ADHD display altered cerebral levels of GABA+ in a subcortical voxel (Bollmann et al. 2015). Additionally, there are also increased cerebral glutamine levels in children with ADHD, but this difference is normalized among adults with ADHD (Bollmann et al. 2015). In other words, suggesting that this alteration might change through development.

There is a plethora of results showing that compounds/interventions that antagonize glutamic acid receptors and/or block the glutamate signal during the “brain growth spurt” or in the adult animal may induce functional and biomarker deficits (Davison and Dobbing 1968; Di Miceli and Gonier 2015; Fredriksson and Archer 2002, 2003; Fredriksson et al. 2004; Pozzi et al. 2011; Zimmermann et al. 2015; Zhou et al. 2011). Normal regional brain development follows an inherited, preprogrammed route that differentiates the specific structural characteristics and functional domains that are expressed in the adult human and animal (Dobbing and Sands 1970, 1979). Any interference with the course of normal brain development threatens the regional structural and functional integrity with more or less permanent consequences for the individual (Chen et al. 1999; Dobbing 1970a, b, c, 1971; Huebner et al. 2015). The period of the “brain growth spurt” starts with the final trimester of pregnancy in humans and continues until about three years after birth (Ikonomidou et al. 2001). The corresponding period in rodents is encompassed by a rapid increase in brain weight, proliferation of astroglial and oligodendrocyte cells, axonal elongation, arborization, and synaptogenesis (Byrnes et al. 2001; Davison and Dobbing 1966). Agents affecting glutamate system are implicated highly in the vulnerability of brain development since chronic prenatal exposure to an ethanol regimen throughout gestation induced suppression of the hippocampal glutamate-NMDA receptor-NOS signaling system, decreased number of hippocampal CA1 pyramidal cells, increased spontaneous locomotor activity, and impaired performance in the Morris water maze (Byrnes et al. 2001; but see also Byrnes et al. 2003, 2004). Anticonvulsant drugs can initiate neuron and oligodendroglia apoptosis, suppress neurogenesis, and inhibit normal synapse development and regional-sculpting (Turski and Ikonomidou 2012). The behavioral correlates in rodents and non-human primates consist of long-lasting cognitive impairment and motor deficits. Physiological apoptosis and that caused by other agents, a naturally occurring process of the developing brain, modulates regional progressions at cellular and circuitry levels periodically (Dikranian et al. 2001; Ishimaru et al. 1999; Olney et al. 2000).

Several studies have demonstrated marked deficits in behavioral domains in the adult animal following disruptions in glutamate signaling and GABAergic activity (Cohen Kadosh et al. 2015; Kim et al. 2015; Tzanoulinou et al. 2015; Zhang et al. 2015) in the prenatal or neonatal human and animal (Higuera-Matas et al. 2015; Jantzie et al. 2015; Keimpema et al. 2014; Kleteckova et al. 2014; Simões et al. 2015). It was shown more than twenty years ago that chronic neonatal treatment with the glutamate antagonist, MK-801 (postnatal days 8 to 19), induced marked alterations of monoamines (Gorter et al. 1992a) whereby dihydroxyphenylacetic acid (DOPAC) concentrations were elevated (greater than 40 %) in both regions (cortex and striatum) tested, while 5-hydroxyindoleacetic acid (5-HIAA) concentration was significantly elevated only in the cortex (19 %), and 3-methoxy-4-hydroxyphenylglycol (MHPG) only in the striatum (47 %). When tested spatial learning and memory using a water maze, the neonatal MK-801-treated rats were shown to be capable of learning the spatial task as well as control rats but did so at a significantly slower rate. Their performance in a visual cue task was not affected by the neonatal treatment, suggesting that the slower spatial learning is not caused by locomotor or sensory deficits (Gorter and de Bruin 1992). The authors interpreted their findings to imply that chronic NMDA receptor blockade during the neonatal period leads to long-lasting disturbances of hippocampal function (but see also Gorter et al. 1991, 1992b). The glutamate antagonists, MK-801 (3 × 0.5 mg/kg), ketamine (1 × 50 mg/kg), and ethanol (2 × 2.5 mg/kg) were administered postnatally to mouse pups on days 10 or 11 postpartum (cf. Fredriksson and Archer 2004), and behavioral testing was performed at adult ages over and above 65 days-of-age. At testing, it was found that over 60-min periods of motor activity testing, the mice administered the glutamate antagonists showed a somewhat bizarre pattern of activity that was completely different to that shown by untreated, saline- or vehicle-treated, or sham-operated mice: The former presented markedly lower levels of motor activity than the latter during the initial period of activity testing (1st 20 min) and then successively greater levels of motor activity than the latter during the middle and final periods of activity testing (2nd and 3rd 20 min periods). Table 1 presents the motor activity, locomotion, and rearing of mice injected postnatally with either MK-801, ketamine, or ethanol expressed as a percentage of each respective vehicle control group. It will be noted that the mice administered glutamate antagonists evidenced massively greater levels of apoptosis (as measured by fluoro-jade positive staining) in several brain regions, including frontal cortex, hippocampus, cerebellum, parietal cortex, and laterodorsal thalamus, compared to controls, 24 h after administration of the drugs, MK-801, ketamine, or ethanol. The results on Table 1 indicate that these animals fail to perform the exploratory activity, observed invariably with control mice, that is associated with introduction to a novel environment (the test cages). Later, when the control animals show less locomotor and rearing activity, i.e., interest in the test cages, the MK-801-, ketamine-, and ethanol-treated mice showed successively greater levels of locomotion and rearing (interest), i.e., they fail to “habituate” effectively, implying a cognitive dysfunction. The cognitive dysfunctionality of the MK-801-, ketamine-, and ethanol-treated mice was demonstrated in both the radial arm maze and the circular swimming maze (Fredriksson and Archer 2004). Spontaneously hypertensive rats (SHRs) present several of the characteristic behavioral anomalies observed in ADHD children and adults: hyperactivity, impulsiveness and poorly sustained attention, restlessness, and comorbid drug self-administration (Grünblatt et al. 2015; Jordan et al. 2015; Womersley et al. 2015).

Table 1 Locomotion and rearing behavior expressed as percent of control values (0.9 % saline-vehicle) over successive 20-min periods in the motor activity test cages by adult mice administered either MK-801, ketamine or ethanol, glutamate antagonists at the doses used, or diazepam, GABA agonist at the doses used. MK-801 (0.5 mg/kg, s.c.) was administered to male mouse pups on postnatal day 11 on three occasions over that day. Ketamine (1 × 50 mg/kg, s.c.) and ethanol (2 × 25 mg/kg, s.c., with a 2-h interval between injections) were administered on postnatal day 10
Full size table

2 Aberrant Glutamate in Spontaneously Hypertensive (SHR) Rats

There is emerging evidence that spontaneously hypertensive (SHR) rats possess disruptions in glutamate systems or in glutamate signaling or in region (e.g., nucleus accumbens) characteristics (Russell 2003). For example, it was observed that the glutamatergic system in the prefrontal cortex of the SHR rats was hyperfunctional (Miller et al. 2014). Sterley et al. (2015) have provided evidence for a disturbed glutamatergic and GABAergic transmission in the hippocampus of SHRs and that maternal separation induced effects on glutamate uptake in these rats and Wister-Kyoto and Sprague-Dawley rats as well. Furthermore, compared to control animals, SHRs displayed a lower expression of both NMDA (Grin1) and AMPA (Gria1) gene receptors in the nucleus accumbens. It has been observed also that SHRs express decreased levels of several proteins involved in energy metabolism, cytoskeletal structure, myelination, and neurotransmitter function when compared to Wistar-Kyoto ratsFootnote 2 (Dimatelis et al. 2015). Liso Navarro et al. (2014) found significant correlations between brain metabolites and the behavior registered in the open field and elevated plus maze: SHR rats expressing higher levels of brain total creatine levels and glutamate levels exhibited higher levels of hyperactivity in a familiar environment, but conversely, risk-taking exploratory behavior, an indication of impulsivity, of the elevated plus maze’s open arms correlated negatively with forebrain total N-acetylaspartate and lactate levels. It has been shown also that there is a reduction in extracellular concentrations of GABA in the hippocampus of SHR rats, in vivo, by comparison with Wistar-Kyoto and Sprague-Dawley rats (Sterley et al. 2013). The authors suggest that an underlying defect in GABA function may be the underlying cause of the dysfunction in catecholamine transmission noted in SHR and may underlie their ADHD-like behaviors (see also Mc Fie et al. 2012; Miller et al. 2012). Ye et al. (2013) observed that there were increases in presynaptic group II metabotropic glutamate receptor activity at the glutamatergic terminals at hypothalamic paraventricular nucleus sites in SHR rats. The activation of group II metabotropic glutamate receptors in the hypothalamic paraventricular nucleus inhibits sympathetic vasomotor tone through attenuation of increased glutamatergic input and neuronal hyperactivity in SHR rats, thereby affecting sympathetic outflow in hypertension and related conditions. In this context, physical exercise was shown to ameliorate the enhancement in the tonically acting glutamatergic input to the rostral ventrolateral medulla of SHR rats, thereby reducing the sympathetic hyperactivity and blood pressure (Zha et al. 2013). Following exposure to the NMDAR antagonist, MK-801, during postnatal days 5–14, to male Sprague-Dawley rat pups (Li et al. 2015), the animals were tested for object and object-in-context recognition memory during adolescence (PND 35) and adulthood (PND 63). They examined also parvalbumin-positive GABA-ergic interneurons and presynaptic markers for excitatory and inhibitory neurons, vesicular glutamate transporter-1, and vesicular GABA transporter in the hippocampus to reflect the excitatory/Inhibitory balance. They observed that rats that had received MK-801 treatment displayed deficits of recognition memory, reduction in parvalbumin-positive cell counts, and upregulation of the vesicular glutamate transporter-1/vesicular GABA transporter ratio in both adolescence and adulthood. It would appear that the changes of the vesicular glutamate transporter-1/vesicular GABA transporter ratio at the two time points exhibited distinct mechanisms. Furthermore, prenatal alcohol exposure affected cortical angiogenesis negatively both in mice and in fetal alcohol syndrome patients, implying that vascular defects contributed to alcohol-induced brain abnormalities (Jegou et al. 2012). Postnatal treatment with domoic acid, which disturbs glutamate signaling, induced deficits in latent inhibition and sensory gating through prepulse inhibition impairments (Marriott et al. 2012).

Finally, several genetic linkage and association studies point to candidate genes relating to ADHD (Franke et al. 2009). Associations between ADHD and a handful of NMDA-R gene variants [GRM1, GRM5, GRM7, and GRM8: encoding G-protein coupled receptor family] (Diana et al. 2015; Akutagava-Martins et al. 2014). Santoro et al. (2015) compared the gene expression profile of neurotransmitter receptors and regulators in the prefrontal cortex and nucleus accumbens of SHR and control Wistar rats, as well as the DNA methylation pattern of promoter region of the genes differentially expressed. They found that four genes were downregulated significantly in the prefrontal cortex of the SHRs in comparison with Wistar rats (Gad2, Chrnb4, Slc5a7, and Qrfpr) and none of those in nucleus accumbens. Gad2 and Qrfpr showed CpG islands in their promoter region. For both of these genes, the promoter region was hypomethylated in SHR rats and may be linked to the abnormalities displayed by these animals. Since adverse life events, dysfunctional families, pregnancy and birth complications, etc, all increase risk for ADHD (Class et al. 2014; Lindström et al. 2011; Pires et al. 2013; Webb 2013), the epigenetic influences upon glutamatergic integrity seems immeasurable (Grissom and Reyes 2013; Schuch et al. 2015). van Mil et al. (2014) examined the association between DNA methylation levels at different regions and ADHD symptoms. They observed that DNA methylation levels were linked negatively with ADHD symptoms scores in the analysis of eleven brain regions.

3 Conclusions and Final Remarks

The notion of a disruption of the normal brain developmental trajectory, due an over-stimulation of GABAergic systems and/or an understimulation (antagonism) of the glutamate systems, i.e., excitatory-inhibitory imbalance, in the underlying pathophysiology of ADHD, particularly regarding motor and cognitive domains, is appealing. The pattern of behavioral deficits when tested as adult animals and “accelerated apoptosis” 24 h after administrations of the glutamate antagonists offers a useful laboratory model of the disorder. Babenko et al. (2015) have offered a plausible account that describes the complex gene–environment interactions between prenatal stress exposure, whether chemical intervention or social-behavioral, associated changes in miRNA expression and DNA methylation in placenta and brain regions together with the possible links to greater risks of schizophrenia, ADHD, autism, anxiety-, or depression-related disorders that may be expressed later in life.

Finally, ADHD is associated with an increased risk of personality disorders and deficits and specific temperament configurations: high novelty seeking and high harm avoidance (Anckarsäter et al. 2006). Individuals high in novelty seeking tend to be highly active or to direct their attention/behaviors in response to novel stimuli, potential rewards, and punishments. This is expressed as frequent exploration of new unfamiliar places or situations, quick loss of temper, impulsive decision-making, and active avoidance of monotony. High levels of harm avoidance are expressed as the tendency to avoid or cease behaviors due to intense response to aversive stimuli expressed as fear of uncertainty, shyness of strangers, quick fatigability, and pessimistic worry of future problems (Cloninger et al. 1993). This “explosive” temperament profile (high novelty seeking and high harm avoidance) does fit in the ADHD pathophysiology outlined in this chapter. What is more, molecular genetics studies have found an association between novelty seeking and the dopamine-4 receptor (Benjamin et al. 1996; Ebstein et al. 1996; Noble et al. 1998; Ono et al. 1997) and between harm avoidance and the serotonin transporter 5HTTLPR (Rybakowski et al. 2006; Samochowiec et al. 2001). Fortunately, recent advances using person-centered interventions (i.e., well-being coaching) suggest that the expression of genes as personality traits can be changed (Cloninger 2004; Wong and Cloninger 2010; see also Fahlgren et al. 2015), In particular when the intervention focuses on the development of character traits, such as self-directedness (e.g., sense of control, self-efficacy, self-acceptance), cooperativeness (e.g., tolerance, helpfulness, empathy), and self-transcendence (e.g., spirituality, meaningfulness, ability to experience flow). Relatedly, changes in mean levels of character traits are much greater between 20 and 45 years of age than for temperament traits (Josefsson et al. 2013). Hence, upcoming studies using person-centered interventions among individuals with ADHD are most welcome.