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ADHD in animal models


ADHD in animal models

There are several rat breeds that represent ADHD-HI, ADHD-I and non-affected as animal models. Among them, SHR and Wystar-Kyoto are mainly the subject of research.
The Spontaneous(ly) hypertensive rat (SHR) represents a form of ADHD-HI (with hyperactivity), while Wistar-Kyoto rats (WKY) usually represent non-affected individuals as an opposite model. In addition, there is an SHR strain, the SHR/NCrl, that shows symptoms of ADHD-C and a strain, the WKY/NCrl, that shows symptoms of ADHD-I (attention deficit without hyperactivity).1234 Unless studies differentiate this, it is regularly assumed that Wistar-Kyoto rats (WKY) refers to the non-affected model.
In rats, the predominant glucocorticoid is corticosterone, instead of cortisol, which is predominant in humans.

The respective rat lines were bred for specific symptoms. The rearing of these animals does not involve any stress.5
That these animal models express their symptoms based on genetic makeup alone and without the influence of early childhood stress is a strong argument that certain genes alone represent a distinct pathway for the development of mental disorders such as ADHD and that the two developmental pathways of genes alone and genes + environment coexist.
Interestingly, the findings about SHR do not weaken the theory that ADHD (like many other mental disorders) causes its symptoms through a disruption of the HPA axis, but strengthen it enormously - because SHR already show a disrupted HPA axis simply because of their genetic predisposition.

ADHD is also discussed in dogs.6

The various animal models show vividly that symptoms such as hyperactivity, impulsivity or attention problems can have very different causes. The mediation of symptoms must be distinguished from the causes (e.g., a specific genetic defect). Thus, very different causes (e.g., gene defects) can cause a dopamine deficit or others can cause a dopamine excess, both of which in turn mediate nearly identical symptoms due to deviation from optimal dopamine levels (inverted-U). To clarify this, we have divided animal models, as far as we know, into those with a dopamine (effect) deficiency and a dopamine (effect) excess. Although dopamine is a particularly important factor in ADHD, the other influences are also relevant.

1. Animal models of ADHD with decreased dopamine levels / decreased dopamine action

By “decreased dopamine” here we mean decreased phasic dopamine in the striatum.
Decreased phasic dopamine in the striatum is accompanied by increased tonic dopamine in the PFC.

1.1. Spontaneous(ly) hypertensive rat (SHR)

SHR exhibits (with the exception of sex differences) all major human ADHD-HI traits (with hyperactivity):

  • Hyperactivity7
    • Develops with age
    • Reduced by MPH and AMP
  • Impulsivity7
    • Impaired ability to withhold reactions7
    • Develops with age
    • Reduced by MPH
  • Inattention7
    • Reduced by MPH
  • Targeted behavior impaired
    • Restored by MPH8
  • Low power stability7

SHR serves as an animal model to study ADHD.910

The Spontaneous(ly) hypertensive rat (SHR) is a strain of rat bred for specific symptoms, beginning in 1963, as an animal model of hypertension.11 The animals have genes that cause them (without early childhood stress experience in old age) to experience increasing hypertension.
in 1992, SHR were found to be a model of ADHD-HI at the same time.12 Since then, SHR have served as a scientific animal model of ADHD-HI (with hyperactivity) in ADHD research.

SHR was developed in 1963 by mating Wistar Kyoto males with marked elevation of blood pressure with females with slightly elevated blood pressure. Subsequently, brothers were mated with sisters under continued selection for spontaneous hypertension.13
That all specimens exhibit identical behavior that stresses young to exactly the same degree should be impossible. Nevertheless, the pathological behavior patterns are present in all specimens.14 This indicates that certain genetic constellations can cause psychological disorders even without the addition of stressful environmental influences, i.e. that the formula genes + environment is a frequent but not exclusive etiological model for psychological disorders.
Interestingly, the first generations of SHR had a massive problem of cannibalism on newborns. This problem has since been solved by keeping pregnant rat mothers in isolation until the young reach a certain age. It would be interesting to know if the SHR also shows special behavior towards young animals in other ways.

With increasing age and in parallel with increasing hypertension, SHR is observed to have an increasing sensitivity of the HPA axis to stress.15
High blood pressure is an organic consequence of chronic stress.16

The SHR could be further bred to a hyperactive and stress-sensitive but less aggressive and nonhypertensive strain (WK/HA) and a hypertensive but nonhypertensive strain (WK/HT) by crossing with WKY strains. MK/HA exhibit alterations in monoamine function, particularly in norepinephrine and dopamine uptake by the PFC. In addition, neuroendocrine responses in the HPA axis and POMC peptides in the anterior and posterior pituitary lobes are altered.1718

The importance of SHR as an ADHD model should be appreciated to the right extent. Just as in humans there should be little doubt that there are very many different ADHD pathways (hundreds, if not thousands, of genes are involved, which may act in very different compositions in affected individuals), the SHR is not the only model animal for ADHD and here ADHD-C. Therefore, the SHR can at best be a possible model for ADHD. If 1000 genes were actually involved (most of which can form several alternative gene variants with different expression profiles), there would be an almost infinite number of possibilities, in purely mathematical terms, for how they could be put together. Certainly not all candidate genes have the same influence and frequency, but the line of thought shows that SHR can be only one of many possible genetic constellations of ADHD.

1.1.1. Dopamine system impaired Dopamine synthesis impaired

In SHR, the miRNA let-7d is reported to be overexpressed in the PFC and the expression of galectin-3 is decreased, leading to downregulation of tyrosine hydroxylase, which is a precursor of dopamine synthesis.19 This results in impaired dopamine synthesis. One study, however, found excessive galectin-3 blood plasma levels in ADHD-affected children.20
The synthesis of dopamine in the brain occurs in two steps. First, the amino acid tyrosine is catalyzed by the enzyme tyrosine hydroxylase and converted into l-3,4-dihydroxyphenylalanine (l-DOPA), then l-DOPA is decarboxylated to produce dopamine.

At day P5 and P7 after birth, decreased tyrosine hydroxylase gene expression was found, and at day P27 to P49, decreased midbrain dopamine transporter (DAT) gene expression was found. In adult SHR, DAT are overexpressed, which decreases dopamine levels in the synaptic cleft.21

Further, in SHR, dopamine uptake in the striatum was markedly reduced in the first month of life.21

SHR showed weaker release of dopamine and acetylcholine in the striatum on glutamate.22 D2 receptor increased

SHR showed significantly increased dopamine D2 receptor expression in PFC, striatum, and hypothalamus. Atomoxetine significantly decreased dopamine D2 gene expression in PFC, striatum, and hypothalamus in a dose-dependent manner.23
Another study did not find increased D2 expression in SHR.21

Another study found that in SHR, postsynaptic D1-/D2-like receptors appear to be decreased in sensitivity, whereas presynaptic dopamine D2-like autoreceptors, which are found primarily in the nucleus accumbens, are arguably increased in sensitivity.24 (Only) D4 receptor reduced in the PFC

SHR showed significantly decreased dopamine D4 receptor gene expression and protein synthesis in the PFC. Other dopaminergic genes in midbrain, PFC, temporal cortex, striatum, or amygdala of SHR were unchanged compared with WKY.25 Dopamine release reduced

In SHR, the dopaminergic presynapses of mesocortical, mesolimbic, and nigrostriatal neurons appear to release less dopamine in response to electrical stimulation/depolarization because of high extracellular K+ concentrations.26

SHR/NCrl showed reduced KCl-evoked dopamine release in the dorsal striatum compared with WKY/NCrl (an ADHD-I model).27 Dopamine uptake in the striatum accelerated

SHR/NCrl showed faster dopamine uptake in the ventral striatum and nucleus accumbens than controls, whereas WKY/NCrl (an ADHD-I model) showed faster dopamine uptake only in the nucleus accumbens.27 This is consistent with increased DAT activity in SHR.

1.1.2. Adenosine system altered in SHR

The adenosine system interacts with the dopamine system.
In SHR, adenosine is increased in blood plasma28 and the amount of adenosine A2A receptors in frontocortical nerve terminals (presynapses).29 The bioavailability of adenosine in vascular tissues and arteries of SHR appears to be increased, whereas at the same time, adenosine transporters (ENT) and A1 and A2A receptors are downregulated. In veins, the expression of ARs and ENTs appears unchanged, whereas the A2A receptor appears to be upregulated and the ENT2 transpprter downregulated.30

Adenosine receptor antagonists improve various ADHD symptoms in SHR

  • Caffeine (non-selective A1 and A2A adenosine receptor antagonist)
    • Object detection31
    • social recognition32
    • spatial learning33
    • no influence on high blood pressure33
  • DPCPX (8-cyclopenthyl-1,3-dipropylxanthine, A1 antagonist)
    • Object detection31
    • no influence on high blood pressure33
  • ZM241385 (4-(2-[7-amino-2-[2-furyl][1,2,4]triazolo-[2,3-a][1,3,5]triazin-5-yl-amino]ethyl) phenol, A2A-Antagonist)
    • Object detection31
    • social recognition32
    • no influence on high blood pressure33

Chronic Caffeine Input:29

  • normalized the dopaminergic function
  • improved memory and attention deficits
  • induced upregulation of A2A receptors in frontocortical nerve terminals

Chronic administration of caffeine or MPH before puberty later improved object recognition in adult SHR, whereas the same treatment worsened it in adult Wistar rats.34

Evidence exists for an interaction between the cannabinoid and adenosine systems in relation to impulsive SHR behavior:35

  • WIN55212-2 (cannabinoid receptor agonist) increased impulsive behavior
  • acute pretreatment with caffeine reversed this
  • chronic caffeine intake increased impulsivity

In SHR, adenosine-mediated presynaptic inhibition of adrenergic transmission appears to be genetically reduced.36
The A1 agonist CPA increased alpha2-adrenoceptor binding in the nucleus tractus solitarius about 10 times more in SHR than in WKY.37

Adenosine affects blood pressure.38 Adenosine decreased blood pressure in SHR even more than in WKY. Adenosine decreased heart rate in SHR and increased it in WKY.((Ohnishi, Biaggioni, Deray, Branch, Jackson (1986): Hemodynamic effects of adenosine in conscious hypertensive and normotensive rats. Hypertension. 1986 May;8(5):391-8. doi: 10.1161/01.hyp.8.5.391. PMID: 3699881.))

1.1.3. Norepinephrine release increased

In the laboratory, PFC brain cells from SHR showed increased norepinephrine release in response to glutamate. This effect was not mediated by NMDA receptors because NMDA did not alter norepinephrine release. It is suggested that the noradrenergic system is overactivated in the PFC of SHR.39

The A1 agonist CPA increased alpha2-adrenoceptor binding in the nucleus tractus solitarius in SHR about 10 times more than in WKY.37Adenosine-mediated presynaptic inhibition of adrenergic transmission appears to be genetically reduced in SHR.40.

In SHR, autoreceptor-mediated inhibition of noradrenaline release appears to be impaired, suggesting poorer regulation of noradrenergic function in the PFC. The behavioral disturbances of ADHD may be the result of an imbalance between noradrenergic and dopaminergic systems in the PFC, with decreased inhibitory dopaminergic activity and increased noradrenergic activity.2641

1.1.4. Serotonin in SHR

SHR show increased numbers of serotonin transporters in the striatum in adulthood, unchanged by MPH.42

1.1.5. GABA in SHR

SHR showed decreased [3H]-GABA uptake and release, suggesting a defective striatal GABA-ergic transport system.
Caffeine improved in vitro in the striatum of SHR the

  • GABA release (intrinsically reduced in SHR)
  • GABA reuptake via GAT1 transporter (reduced in SHR per se)

whereas this was not the case in Wistar rats (which are not an ADHD animal model).43

One study found evidence that extracellular concentrations of GABA may be reduced in the SHR hippocampus. An underlying defect in GABA function could be the cause of the dysfunction of catecholamine transmission found in the SHR and underlie their ADHD-like behavior.44

1.1.6. Vitamin D3 metabolism altered in SHR

In SHR, 25-hydroxyvitamin D-1-alpha-hydroxylase activity appears to be decreased. This could be due to impaired renal metabolism or responsiveness to cyclic adenosine 3’,5’-monophosphate. In SHR as in WKY, a one-week restriction of dietary phosphorus resulted in an increase in plasma D3 concentration. There was no change in blood pressure as a result.45 Another study found increased as well as decreased D3 levels.46

1.1.7. Stress systems changed Overintense HPA axis stress response in SHR compared with WKY

7-week-old SHR show significantly compared to WKY of the same age47

  • Increased corticosterone responses to hemorrhage and ether stress
    Note: Because SHR represent a model for ADHD-HI and not ADHD-I, we would expect flattened stress corticosterone responses as found in other studies48
  • Elevated basal corticosterone levels
    Note: Decreased basal cortisol levels are usually found in people with ADHD regardless of subtype
  • Decreased plasma ACTH responses to hemorrhage and ether stress
  • Lower plasma ACTH responses to iv CRH injection
  • Identical plasma ACTH responses to vasopressin
  • Lower CRH concentrations in hypothalamus (median eminence), posterior pituitary and cerebral cortex
  • Decreased CRH release from the hypothalamus
  • Identical CRH response to 56 mM KC1

If the adrenal glands, which are the source of glucocorticoids for the HPA axis, were removed in both species, the

  • The ACTH response to stress identical
  • The CRH concentrations in hypothalamus (median eminence) identical
  • Prevented the development of hypertension in SHR

Corticosterone given as a replacement restored the blood pressure elevation in SHR.

Dexamethasone as a glucocorticoid receptor (GR) agonist improved ADHD-HI symptoms in SHR.49 A GR antagonist (mifepristone) elicited ADHD-HI symptoms in other rat species (not otherwise exhibiting ADHD symptoms).50

These results indicate that,

  • That the HPA axis is overactivated in young SHR
  • That a reduced ACTH response to stress, as to CRH, is due to higher plasma corticosterone levels
  • And that glucocorticoids are essential for the development of hypertension in SHR
  • That in ADHD-HI (with hyperactivity), the GR receptor may be under-addressed, whether due to insufficient number or sensitivity of GRs, or excessive number of MRs

Other studies observed significantly decreased basal levels of in SHR14

  • Aldosterone at 8 weeks of age
  • 18-hydroxy-lldeoxycorticosterone (18-0H-D0C)1 at 12 weeks of age
  • Deoxycorticosterone (DOC) at 20 weeks of age
  • Corticosterone at 12 and 20 weeks of age. Increased mineralocorticoid receptor expression as a cause of hyperintense HPA axis stress responses in SHR

SHR genetically have excessive expression of mineralocorticoid receptors (MR) and normal expression of glucocorticoid receptors (GR).51
Accordingly, a shift in the balance between MR and GR toward increased MR leads to increased basal and stress-responsive activity of the HPA axis.
Corticosteroid receptor hypothesis of depression

Dexamethasone as a glucocorticoid receptor (GR) agonist improved ADHD-HI symptoms in SHR. In a mirror image, a GR antagonist (mifepristone) elicited ADHD-HI symptoms in other rat species (which otherwise do not exhibit ADHD symptoms).50

This is consistent with our view that ADHD-HI (with hyperactivity) is caused or controlled by a worsened response of GR relative to MR.
We wonder whether ADHD-I might be inversely characterized by a reduced number of MR relative to GR.

MR regulate the day-to-day activities of cortisol. GR, on the other hand, are only addressed when cortisol levels are very high and have the function of shutting down the HPA axis again. In the presence of MR overload and a reduced cortisol stress response (typical of ADHD-HI), the unoccupied MRs soak up cortisol so that the GRs are not sufficiently occupied to trigger HPA axis shutdown.
In contrast, if MRs are underrepresented or if the cortisol stress response is excessive (as in ADHD-I), GRs are addressed too quickly and the HPA axis is shut down too frequently. MiRNA expression in SHR alters glucocorticoid receptor

For the miRNA

  • MiR-138
  • MiR-138*
  • MiR-34c*
  • MiR-296
  • MiR-494

significantly decreased expression was found in the ADHD rat model of SHR, which was related to promoter inhibitory activity of the glucocorticoid receptor Nr3c1.52

SHR, corticosterone and stress sensitivity

Castrated or sterilized SHR showed decreased blood pressure and increased basal corticosterone levels,53 which, in our opinion, contrary to the authors’ conclusion, may suggest that insufficient basal corticosterone levels (and insufficient response intensity of the HPA axis) may cause the hypertension. In addition, the relationship between stress, sex hormones, and mental disorders is clarified.

The decreased basal corticosterone level in SHR or cortisol level in people with ADHD-HI may result from increased glucocorticoid 6-beta hydroxylation (increased family 3A cytochrome P-450 activity). SHR respond to injected [3H] corticosterone with urinary excretion of 6β- [3H] OH-corticosterone four to five times greater than control Wistar-Kyoto rats, consistently before as well as after the development of hypertension.
Hypertension as well as 6-beta hydroxylation could be inhibited by selective 3A P-450 - cytochrome inhibitors.5455

SHR are much more sensitive to heat or other stressors56 which correlates with the increased sensitivity present in ADHD.

1.1.8. SHR and immune system Young SHR

Young SHR show in comparison to WKY57

  • Increased levels of cytokines
  • Increased levels of chemokines
  • Increased levels of markers for oxidative stress
  • Reduced PFC volumes
  • Increased levels of dopamine D2 receptors. Older SHR

Older SHR show in comparison to WKY57

  • Normalized levels of cytokines
  • Normalized levels of chemokines
  • Normalized levels of markers for oxidative stress
  • Increased levels of steroid hormones. Other altered immune values in SHR

In the animal model of ADHD-HI (with hyperactivity), the Spontaneous(ly) hypertensive rat (SHR) was found in brain regions (not peripheral blood) in adult male animals:58

  • Increased levels of reactive oxygen species (ROS) in cortex, striatum and hippocampus
  • Decreased glutathione peroxidase activity in the PFC and hippocampus
  • Decreased TNF-α levels in the PFC, the rest of the cortex, hippocampus and striatum
  • Decreased IL-1β levels in the cortex
  • Decreased IL-10 levels in the cortex. Taurine improved inflammatory markers in SHR

SHR rats treated with taurine showed decreased serum levels of C-reactive protein (CRP) and IL-1β.59 While low levels of taurine increased motor activity, high levels of taurine decreased it.

1.1.9. Cholesterol metabolism altered in PFC of SHR; MPH revises change

One study found 12 altered metabolites in PFC in SHR (compared with WKY). The deviations of 7 of them were equalized by MPH:60

  • 3-Hydroxymethylglutaric acid
  • 3-phosphoglyceric acid
  • Adenosine monophosphate
  • Cholesterol
  • Lanosterol
  • O-Phosphoethanolamine
  • 3-hydroxymethylglutaric acid.

The altered metabolites belong to the metabolic pathways of cholesterol.
In the case of SHRs, the PFC found that

  • Reduced activity of 3-hydroxy-3-methyl-glutaryl-CoA reductase
    • Unchanged by MPH
  • Decreased expression of sterol regulatory element-binding protein-2
    • Increased by MPH
  • Decreased expression of the ATP-binding cassette transporter A1
    • Increased by MPH.

1.1.10. Blood pressure, sympathetic nervous system, cardiac hypertrophy and vitamin D3 in SHR

In SHR, compared with WKY rats, found to be

  • Increased systolic blood pressure
  • Increased sympathetic drive
  • Cardiac hypertrophy and cardiac remodeling.

These abnormalities correlated in the paraventricular nucleus of the hypothalamus (PVN) with

  • Higher mRNA and protein expression levels of
    • High mobility box 1 (HMGB1)
    • Receptor for advanced glycation end products (RAGE)
    • Toll-like receptor 4 (TLR4)
    • Nuclear factor-kappa B (NF-κB)
    • Proinflammatory associated cytokines
    • NADPH oxidase subunit
  • Increased level of reactive oxygen species
  • Microglia activation

as well as with

  • Increased level of norepinephrine in the blood plasma.

These phenomena could be eliminated by an infusion of 40 ng of calcitriol daily.61

40 ng calcitriol corresponds to 0.04 micrograms vitamin D3. At a weight of about 200 g / rat, this should correspond to 0.2 micrograms / kg body weight. The recommended daily dose of D3 for humans is 0.12 to 1 microgram with close medical supervision, which would correspond to a daily dose of 0.0125 microgram / kg body weight at 80 kg. The D3 dosage used in the study therefore corresponds to 16 times the upper limit of the daily dose recommended in humans. At such a dosage, considerable health risks would have to be expected in humans.

1.1.11. Brain regions reduced in size

An MRI scan showed that the vermis cerebelli, nucleus caudatus, and putamen were significantly reduced in SHR.25

1.1.12. Brain connectivity impaired locally as well as widely

With functional ultrasound imaging, which allows rapid measurement of cerebral blood volume (CBV), was found in SHR:62

  • increased response to visual stimulation in visual cortex and superior colliculi
  • functional connectivity
    • changed over long distances between spatially separated regions
    • local / regional connectivity changed
      • regional homogeneity
        • strongly increased in parts of the motor and visual cortex
        • in the secondary cingulate cortex, the colliculi superiores and the area pretectalis reduced

1.1.13. PFC neurons altered

PFC neurons of SHR showed fewer neurite branches, shorter maximum neurite length, and lower axonal growth than PFC neurons of WKY
The adenosine antagonist caffeine restored neurite branching and extension in SHR neurons via PKA and PI3K signaling.
The A2A agonist CGS 21680 enhanced neurite branching via PKA signaling
The selective A2A antagonist SCH 58261 restored axonal growth of SHR neurons via PI3K- alone (not by PKA signaling).63

1.1.14. Thyroid hormones increased

SHR/NCrl - Rats (ADHD-HI, hypertension) as well as Wistar-Kyoto rats (WKY/NCrl) (inattention) show increased expression of the thyroid hormone gene (THRSP). A line of mice overexpressing the THRSP gene (THRSP-OE) in the striatum showed inattention in novel object recognition and the Y-maze test, but no hyperactivity in the open-air test and no impulsivity in the cliff avoidance and delay restriction task. Expression of dopamine-related genes (genes for dopamine transporters, tyrosine hydroxylase, and dopamine D1 and D2 receptors) increased in the striatum. Methylphenidate (5 mg/kg) improved attention and normalized expression of dopamine-related genes in THRSP-OE mice.2

1.1.15. Monosodium glutamate affects aggression in a vagus nerve-dependent manner

SHR were given monosodium glutamate (glutamate as a flavor enhancer) during the developmental phase (from day 25 for 5 weeks). This resulted in reduced aggressive behavior. Fear behavior remained unchanged. However, when the vagus nerve was previously cut (vagotomy), monosodium glutamate did not reduce aggression, suggesting mediation of the effect of monosodium glutamate on aggression by the gut-brain axis.64

1.1.16. Drug effect on SHR Effect of MPH on SHR

SHR respond to MPH:

  • Increased attention and memory65
  • Reduced impulsivity in a dose-dependent manner65
  • Hyperactivity
    • Unchanged at low and medium doses65
    • Increased at high doses65
    • Reduced at very high doses12
  • Goal-directed behavior restored by MPH8

Contrary to the view of the meta-study authors, we see no reason to question SHR as a model of ADHD-HI. Since ADHD is multifactorial and SHRs are merely an animal model bred for specific symptoms, SHRs can only represent one variant of ADHD (which moreover corresponds to ADHD-HI rather than ADHD-I). At the same time, it follows that the effects in SHR cannot be transferred to all ADHD sufferers, but that the neurophysiological mechanisms mediating individual symptoms and effects must be considered.

MPH before puberty was able to normalize the otherwise increased DAT density in the striatum in adulthood. The improvement was more pronounced in the SHR/NCrl (serving as a model of the mixed type) than in the WKC/NCrl rat, which serves as a model of the ADHD-I subtype.4

Serotonin transporters in the striatum were not altered by MPH even with long-term administration.42 Effect of amphetamine drugs on SHR

Amphetamine medications caused a reduction in hyperactivity in SHR.12 Effect of atomoxetine on SHR

Atomoxetine produced a reduction in hyperactivity.23

1.1.17. SHR exhibit behavioral subgroups corresponding to ADHD-HI and ADHD-I

One study found subgroups on SHR that differed significantly in terms of impulsivity. Impulsive SHR showed no behavioral subgroups compared with nonimpulsive SHR and WKY (as controls, with WKY showing no behavioral subgroups):66

  • Reduced noradrenaline levels
    • In the cingulate cortex
    • In the medial-frontal cortex
  • Reduced serotonin turnover
    • In the medial-frontal cortex
  • Reduced density of CB1 cannabinoid receptors
    • In PFC
    • Acute administration of a cannabinoid agonist decreased impulsivity in impulsive SHR, with no change in WKY

Since SHR are not gene-identical, cloned animals, but a strain bred for specific symptoms, whose individual animals thus still contain certain genetic differences, the subtypes could also be of genetic origin. So far, however, no heritability has been established for stress endophenotypes (typically more externalizing or internalizing stress response, corresponding to the ADHD-HI subtype/ADHD-C and the ADHD-I subtype)

The reduced norepinephrine level in ADHD-I subtypes of SHR appears to be consistent with Woodman’s findings:

  • Aggression and outward anger correlate with elevated norepinephrine67
  • Anxiety, on the other hand, correlates with increased adrenaline67

1.2. WKY/NCrl - Rats

WKY/NCrl represent an animal model for the ADHD-I subtype (attention deficit without hyperactivity).234

1.2.1. Increased tyrosine hydroxylase in WKY/NCrl

WKY/NCrl show increased tyrosine hydroxylase gene expression as adults.4

1.2.2. Increased DAT in adulthood from WKY/NCrl

WKY/NCrl show increased DAT gene expression at day P25, but not as much increased as SHR/NCrl. Two weeks of treatment with MPH decreased DAT, with a greater reduction when administered before puberty.4

1.2.3. Dopamine release in the striatum unchanged

Unlike SHR/NCrl, KY/NCrl did not show reduced KCl-evoked dopamine release in the dorsal striatum compared with WKY/NHsd controls.27

1.2.3. Dopamine uptake increased (only) in the nucleus accumbens

Whereas WKY/NCrl (an ADHD-I model) showed faster dopamine uptake than controls in the nucleus accumbens only, SHR/NCrl showed faster dopamine uptake in the nucleus accumbens and ventral striatum.27

1.3. DAT-KO Mouse / DAT-KO Rat

DAT-KO mice/rats are often cited as models for increased dopamine levels. This is also correct, but related to the extracellular and thus tonic dopamine level in the striatum. In the interest of comparability of animal models, we take phasic dopamine in the striatum as a reference point, which is significantly decreased in DAT-KO model animals.

The dopamine transporter knockout mouse or rat (DAT1 KO) serves as an animal model to study ADHD.910

The DAT-KO mouse, whose dopamine transporter is nearly deactivated in monozygous animals and approximately halved in heterozygous animals, shows:686970

  • Symptomatology
    • Hyperactivity, spontaneous in unknown environment71
      • However, hyperactivity was only evident in mice that had no DAT at all or 90% less DAT and whose extracellular (tonic) dopamine levels were thus increased 5-fold or at least doubled. Mice that had 50% of the usual number of DAT also had doubled extracellular dopamine levels, but did not exhibit hyperactivity.
        Motor function is controlled by dopamine changes in the subsecond range, i.e., by phasic dopamine, which typically originates from the storage vesicles because it cannot be synthesized so quickly. 50% DAT should be able to replenish the vesicles much better than 10% DAT. This may explain why the two mouse strains differed in terms of hyperactivity despite equally doubled extracellular dopamine levels. Mice with 30% increased DAT showed hypoactivity in novel environments. However, mice with a doubled DAT number showed no variation in hyperactivity or hypoactivity.72
      • Hyperactivity in DAT-KO mouse as in DAT-KO rat remediable by
        • AMP and MPH6873 74
          • Indicating that stimulants do not act alone as dopamine reuptake inhibitors
            • In DAT-KO mice, amphetamine and methylphenidate reduced hyperactivity (occurring only in novel environments), while causing hyperactivity and stereotypy in normal mice. One study suspects that this calming effect is serotonergically mediated. Similarly, stimulants do not reduce the elevated extracellular dopamine levels in DAT-KO mice.74
            • In rats whose dopaminergic cells were chemically destroyed (causing ADHD symptoms75, serotonin and norepinephrine reuptake inhibitors (but not dopamine reuptake inhibitors) decreased hyperactivity (in novel environments), whereas they did not in normal mice, and dopamine reuptake inhibitors actually increased hyperactivity.76
        • A TAAR1 receptor agonist68
        • Haloperidol68
          • Haloperidol increases extracellular DA concentration in the dorsal caudate more effectively than that in the PFC.77
        • Non-selective serotonin receptor agonist 5CT78
        • Not by dopamine or norepinephrine reuptake inhibitors41
          • Such as atomoxetine78
      • Indifferent locomotor activity in response to cocaine and AMP69
      • Non-focal, conservative movement patterns71
    • Impulsivity74
    • Increased reactivity and aggression rates after mild social contact79
    • Cognitive impairments
      • Impaired erasure of habit memory80 with otherwise unchanged learning behavior
      • Deficits in spatial learning74
      • Memory deficits74 and impairments in spatial cognitive function in the radial labyrinth
      • Slightly increased long-term potentiation and strongly decreased long-term depression at excitatory hippocampal CA3-CA1 synapses81
        • Which can cause learning and memory problems, such as difficulty adapting to changes in the environment
        • The dopamine antagonist haloperidol prevented these effects
      • Increased long-term potentiation in the nucleus accumbens82
      • Improving cognitive impairment through:78
        • Atomoxetine
        • Stimulants
        • Guanfacine ( alpha2A-adrenoceptor agonist)83
          • In contrast, worsening by alpha2A-adrenoceptor antagonist yohimbine
      • No improvement in cognitive impairment by:78
        • Non-selective serotonin receptor agonist 5CT
    • Reward motivation deficits
      • Tendency to hedonic positive taste in food84
      • Increased resistance to extinction of food-stressed operant behavior80
      • Sucrose preference
        • Increases85
        • Reduces86
      • Increased reward responses to selective norepinephrine and serotonin blockers87
    • Sleep impaired
      • Reduced sleep:87
        • Non-REM sleep
        • REM sleep
        • Lower total sheep time
      • No wakefulness effect from87
        • Modafinil
        • Methamphetamine
        • The selective DAT blocker GBR12909
      • Excessive wake-promoting effect of87
        • Caffeine
      • Normal circadian patterns of inactivity and activity87
    • Compulsive behavior86
      • Rigid pattern behavior
      • Compulsive stereotypies in delay reward tasks
  • Neurophysiological changes
    • In the dopamine system
      • Increased extracellular dopamine levels to 5 to 6 times8170 in the striatum8179
      • Reduction of tissue dopamine levels to below 5%70
        • Reduced to 1/20 the amount of dopamine in the storage vesicles usually refilled by the DAT, which reserve dopamine for phasic release, making dopaminergic functions totally dependent on the limitations of dopamine synthesis72
      • Reduction of phasic dopamine release to 25%70, corresponding to 1/4 reduced amplitude of evoked dopamine release72
      • Extended lifetime of dopamine in the synaptic cleft by 300 times70
        • Inhibition of serotonin transporters, norepinephrine transporters, MAOA, or COMT did not alter dopamine degradation. This seems to occur more by diffusion in the absence of DAT in the striatum70
      • Increased tonic dopamine extracellular = outside the synaptic cleft88
      • Decreased phasic dopamine = in synaptic cleft88
        • Decreased phasic dopamine release to electrical stimulation, equivalent to hypodopaminergic dysfunctionality89 as seen in SHR and coloboma mice90
      • Medium-sized spike-bearing projection neurons (the most common class of dopamine receptive neurons, such as D1 receptor, D2 receptor, and DARPP-32)91 show high-grade localized loss of spines (spikes) on the dendrites of the proximal segment, but no overall morphological change in terms of dendrite length, number, or overlap, or in synapse-to-neuron ratio.92
      • Downregulation of D1 receptors by 50%69 in the striatum79
      • Downregulation of postsynaptic D2 receptors in the striatum by 50%.41
      • Downregulation of (presynaptic) D2 autoreceptors93 in the striatum79
      • Decreased postsynaptic density of PSD-95 in the striatum and nucleus accumbens, as occurred in other models of increased dopamine levels82
    • BDNF
      • In PFC
        • Decreased BDNF gene expression94
        • Total BDNF and BDNF exon IV mRNA levels reduced95
        • MRNA levels of BDNF exon VI unchanged95
        • Decreased mBDNF levels and decreased trkB activation95
        • Decreased activation of αCaMKII in the PFC95
      • In the dorsolateral striatum
        • MBDNF level in the homogenate increased95
        • MBDNF level in the cytosol increased95
        • MBDNF levels in the postsynaptic density reduced.95
      • TrkB expression in the dorsolateral striatum postsynaptically reduced95
        • TrkB is a high-affinity BNDNF receptor
    • PSD-95 expression postsynaptically reduced in the dorsolateral striatum95
      • PSD-95 is an index of glutamate spin density and measures the interaction between dopaminergic and glutamatergic systems in the striatum, which is important for cognitive processing
    • Decreased GHRH levels96
      • Dopamine receptors in the hypothalamus inhibit the release of GHRH in the hypothalamus97
    • Deficient sensorimotor gating as measured by prepulse inhibition (PPI) of startle response71
    • Anterior pituitary underdeveloped96
      • The anterior pituitary (the adenohypophysis) is a part of the HPA axis (stress axis)

Quite a few of these features were found (to a lesser extent) in mice with only reduced DAT and doubled extracellular dopamine levels.70

The symptoms of DAT-KO mouse could be explained by:72

  • A increased tonic dopamine level, which (due to the exhausted salivary vesicles) is accompanied by a decreased phasic dopamine level, so that too little dopamine is available for short-term steering tasks.
    Due to the lack of DAT, the remaining dopamine stores in the vesicles used for phasic release are completely dependent on the re-synthesis of dopamine
    • This could correspond to the situation after (partial) death of dopaminergic cells, such as after encephalitis, which is also associated with hyperactivity. A (partial) death of dopaminergic cells is accompanied by a significant reduction in the number of dopaminergic presynapses and the corresponding dopamine reuptake sites98.
    • This may further correspond to the model of mice neonatally treated with the DAT toxin 6-hydroxydopamine (6-OHDA), which show hyperactivity and cognitive impairment for a time thereafter.
  • Of indirect regulation of dopaminergic neurotransmission by noradrenergic and serotonergic74 mechanisms of AMP and MPH.
  • From a reduction in exocytotic dopamine release due to decreased phosphorylation of synapsin99

Studies in other mouse strains that have more DAT than DAT-KO mice but have less DAT than wild mice showed that the number of DAT correlates with decreased basal dopamine levels, and as DAT number increases, basal dopamine levels decrease.72

Methylphenidate and amphetamine medication remediate hyperactivity in the DAT-KO mouse (= DAT(-/-) mouse). MPH was also able to remedy and normalize the learning impairment in shuttle-box avoidance behavior. Here, the effective dose of MPH increased extracellular dopamine in the PFC but not in the striatum, whereas MPH increased dopamine in the PFC and striatum in the DAT(+/-) and DAT(+/+) mice.100 The authors discuss that MPH, which also acts as a norepinephrine reuptake inhibitor, may have inhibited NET in the PFC, thereby causing the therapeutically effective dopamine increase in the PFC. NET also degrade dopamine in the PFC. Another option would be that the increased norepinephrine in the PFC due to NET inhibition could have mediated the therapeutic effect.
On the other hand, DAT-KO mice suffer from an extremely high level of dopamine in the striatum, which did not decrease even when the level of dopamine in the PFC was increased.

1.4. DAT (+/-) Mouse

DAT (+/-) mice, unlike DAT-KO mice, still have dopamine transporter function present but reduced compared with wild type (DAT hypofunction).

DAT (+/-) mice showed101

  • Hyperactivity
    • Starting already before the youth
    • Remediable by amphetamines
  • Unchanged reactions to external stimuli
  • Unchanged sensorimotor gating abilities
  • General cognitive impairment
    • In juvenile males and females
    • Partially improved in adult males
      • Attention deficits remained evident
      • Impulsivity remained evidently increased
    • Unchanged in adult females
    • Remediable by amphetamines
  • Reduced expression of Homer1a
    • In PFC
    • Not in other brain regions (striatum)
    • Amphetamines shifted Homer1a expression reduction of PFC in striatum
  • ARC and Homer1b unchanged

1.5. Coloboma mice (CM)

The Coloboma mouse mutant (Cm) serves as an animal model for ADHD research.91041
Cm mice show a mutation in the SNAP-25 gene and are viable only in the heterozygous form. The relationship between SNAP-25 and ADHD is unclear. NAP-25 is a presynaptic protein that regulates the exocytotic release of neurotransmitters; coloboma mice have only 50% of normal protein levels.

Cm mice show the following symptoms:102

  • Impulsivity
    • Different Russell et al41
  • Inhibition problems
  • Probably also inattention
    • Different Russell et al41

Cm mice show compared to control mice:103

  • Changes in the HPA axis103
    • No CRH elevation in the hypothalamus due to acetylcholine
    • More elevated plasma corticosterone levels due to exercise restriction stress
  • Changes in the dopamine system
    • Reduced release of glutamate by (K+) depolarization in cortical synaptosomes [156]
    • DRD2 Expression104
      • Increased in VTA
      • Increased in the substantia nigra
        -> suggesting increased inhibition of the firing rate of dopamine neurons
      • Unchanged in striatum
    • DRD1 expression
      • Unchanged in striatum104
    • Dopamine release
      • Reduced in the striatum[156,158]
        • Reduced only dorsally, not ventrally103
      • In the nucleus accumbens is reduced104
      • Dopamine metabolites DOPAC and HVA decreased in the striatum
        -> consistent with decreased dopamine release and decreased dopamine turnover105
        -> hypofunctional dopaminergic system, similar to SHR41
    • Expression of the tyrosine hydroxylase gene104
      • In the VTA unchanged
      • In the substantia nigra unchanged
      • Increased in the locus coeruleus
  • Changes in the noradrenergic system
    • Expression of α2A-adrenoceptors increased in the locus coeruleus104
    • Noradrenergic function seems to be increased
      • Experimental withdrawal of norepinephrine by DSP-4 reduces hyperactivity but does not completely abolish it106
    • Norepinephrine levels increased in striatum and nucleus accumbens104
  • Changes in the serotonergic system
    • Markedly reduced serotonin levels in the dorsal but not in the ventral striatum103

1.6. 6-OHDA mouse

6-OHDA mice are mice in which dopaminergic cells are destroyed 5 days after birth using 6-hydroxydopamine. They are also considered ADHD models and show symptoms:41107102

  • Hyperactivity (in the open field)108
    • Initially reduced, increased with repetitions
    • Improved by MPH and AMP
    • Unchanged by DAT reuptake inhibitors
    • Reduced by:41
      • DRD4 antagonists
      • Serotonin transporter reuptake inhibitor
      • Norepinephrine transporter reuptake inhibitor
        • Also causes decreased dopamine uptake into noradrenergic presynapses in, among other places
          • PFC
          • Nucleus accumbens
  • Attention deficit in old age
  • Impulsivity in old age (five-choice serial reaction time task)
  • Anxiety-like behavior (in the elevated plus maze test)
  • Antisocial behavior (in social interaction)
  • Decreased cognitive functions (problems with recognition of novel objects)
  • Learning difficulties in a spatial discrimination task
    • Improved by MPH and AMP

Neurophysiological changes:

  • Changes in the dopamine system
    • Dopamine deficiency in the striatum and nucleus accumbens108
    • DRD4 expression increased in caudate nucleus and putamen109
      • A selective D4 antagonist decreased hyperactivity, a D4 agonist increased it109
    • D2 receptor expression not increased109
    • Dopamine reductions, as typical in ADHD107102
    • Changes in cortical thickness, as typical in ADHD107102
    • Abnormalities in the neurons of the anterior cingulate cortex, as typical in ADHD107102
  • Changes in the serotonin system
    • Serotonin transporter:110
      • Binding increased in the striatum
      • Binding unchanged in PFC

1.7. Tal1cko mice

Most GABAergic neurons in the dopaminergic nuclei of the midbrain depend on the transcription factor Tal1 for their formation. Tal1 functions here as a cell fate selector gene that promotes GABAergic differentiation at the expense of alternative glutamatergic neuron identities. Brainstem nuclei harboring Tal1-dependent neurons have been implicated in the control of dopamine neurons and in the regulation of movement, motivated behavior, and learning.
Mice carrying En1Cre16 and Tal1flox11 alleles were crossed to generate En1Cre/+; Tal1flox/flox (Tal1cko) mice. In the Tal1cko mice, the En1Cre allele drives recombination in a tissue-specific manner in both midbrain and rhombomere 1, but this leads to a failure of GABAergic neurogenesis in the brainstem only in embryonic rhombomere 1.
Tal1cko mice showed:111

  • Hyperactivity
  • Increased motor impulsivity
  • Changed reaction to reward
  • Delay discounting (delay aversion)
  • Impaired learning
  • The ADHD-typical paradoxical calming response to pharmacologically stimulated dopamine release by amphetamine and atomoxetine
  • Developmental changes in anterior brainstem GABAergic and glutamatergic neurons.
    These are involved in
    • Regulation of the dopaminergic pathways
    • Basal Ganglia Outpout
  • Lower body temperature
  • Lower body temperature rise during stress
  • Lower nesting
  • Lower grooming (brooding/grooming behavior)
  • Decreased levels of dopamine and dopamine metabolites in
    • Nucleus accumbens (most prominent)
    • Dorsal striatum
    • PFC
  • Unchanged number of dopaminergic cells in
    • Substantia nigra
    • Ventral tegmentum
  • Unchanged serotonin and 5-HIAA levels in
    • Dorsal striatum
    • Nucleus accumbens
    • PFC
  • Unchanged noradrenaline level in
    • PFC
  • Unchanged social behavior

1.8. THRSP-OE Mice

A line of mice with overexpressed THRSP gene in the striatum (THRSP-OE) showed inattention in novel object recognition and Y-maze test, but no hyperactivity in the open-air test and no impulsivity in the cliff avoidance and delay restriction task. Expression of dopamine-related genes (genes for dopamine transporters, tyrosine hydroxylase, and dopamine D1 and D2 receptors) in the striatum was increased. Methylphenidate (5 mg/kg) improved attention and normalized expression of dopamine-related genes in THRSP-OE mice.2
We tentatively conclude from increased DAT gene expression to dopamine deficiency in the striatum.

1.9. SORCS2 -/- Mice

The SORCS2 gene is a candidate gene for ADHD-HI and is also associated with bipolar disorder, schizophrenia, and and symptoms of alcohol withdrawal.
SORCS2 influences the outgrowth of neurites in the brain. During embryonic development, SORCS2 is expressed in dopaminergic precursors of the later ventral tegmentum and substantia nigra.

SORCS2-/- mice have a severe deficiency of Sorcs2. This causes significant changes in the dopaminergic system.
Embryos of SORCS2-/- mice were found to have increased midbrain projections expressing tyrosine hydroxylase. In adult SORCS2-/- mice, the frontal cortex is hyperinnervated (supplied with more nerve fibers), arguing for a critical role of SORCS2 in growth cone shrinkage (the branched tip of an outgrowing axon of a neuron) during dopaminergic innervation.112
SORCS2-/- mice show112

  • Hyperactivity in new environment
    • Is reduced by amphetamine administration
  • Risk appetite
  • Inattention
  • Reduced interest in sugar

Neurophysiologically, SORCS2-/- mice showed 112

  • D1 receptor sensitivity reduced
  • D2 receptor sensitivity increased
  • Decreased phasic and increased tonic dopamine signaling in the ventral tegmentum
    • Tonic dopamine release provides a stable baseline level of extrasynaptic dopamine
    • Phasic (rapid, high-amplitude, intra-synaptic) dopamine release is involved in reward and goal-directed behavior

1.10. ICR mice

ICR mice are more motor active than C57BL/6J or CBA/N mice
ICR mice showed increased levels of L-tyrosine, a dopamine precursor, and decreased dopamine levels in striatum and cerebellum. Administration of L-dopa improved hyperactivity in ICR mice and increased dopamine levels in cerebellum, hippocampus, striatum, and PFC. Administration of BH4 increased dopamine levels in the cerebellum and hippocampus but did not alter behavior. BH4 did not affect serotonin levels.113

2. Animal models with increased dopamine levels

By increased dopamine levels, we mean (phasic) dopamine levels in the striatum.

2.1. LPHN3 knockout rat

The Sprague-Dawley LPHN3 knockout rat exhibits learning and memory deficits and increased dopamine release and dopamine reuptake in the striatum,114 as well as hyperactivity.115
LPHN3-KO rats showed higher DA release with reduced duration compared with wild-type rats.114

2.2. P35-KO mouse

Mice that cannot produce the P35 protein (P35-KO mouse) show spontaneous hyperactivity that can be reduced by MPH and AMP.116 They have increased dopamine levels with decreased dopamine turnover and concomitant decreased CDK5 activity. The number of DAT in the striatum and thus dopamine reuptake is decreased.117
In vitro, inhibition of Cdk5 activity in N2a cells caused a significant increase in constitutive DAT endocytosis with a concomitant increase in DAT localization in recycling endosomes 117

3. Animal models with unknown influence on dopamine levels

In subsequent animal models, we have not yet been able to determine whether (phasic) dopamine levels in the striatum are increased or decreased.

3.1. GIT1 KO mouse

The G-protein coupled receptor kinase 1 knockout mouse (GIT1 KO) serves as an animal model for ADHD research.910
The GIT1 KO mouse shows hyperactivity, learning disabilities, and memory loss as ADHD symptoms. The hyperactivity in GIT1 KO mice is remediable by amphetamine and methylphenidate.118
GIT1 regulates dopamine receptors. Overexpression of GIT1 interferes with the internalization of numerous G protein-coupled receptors, including dopamine receptors.119 The latter suggests a model of reduced dopamine action.

3.2. ATXN7 Overexpressed Mouse

The ATXN7 Overexpressed mice (ATXN7-OE) feature

  • Hyperactivity
  • Impulsivity
  • no inattention

Dires corresponds to the ADHD-HI subtype.
Ataxin-7 gene (ATXN7) correlates with hyperactivity. ATXN7-OE mice have overexpression of the Atxn7 gene and protein in the PFC and striatum. Atomoxetine (3 mg/kg, intraperitoneal) decreases ADHD-HI-like behavior and ATXN7 gene expression in the PFC and striatum.120

3.4. Grin1 mouse

Grin1 mice are a heterozygous mutant strain. Grin1 (glutamate [NMDA] receptor subunit zeta-1) encodes a protein required for NMDA receptor function. Grin2B may be associated with ADHD. Grin1 mice show:

  • Hyperactivity121
  • Novelty seeking121
  • Reduced social interaction121
  • Anxiety122

The attentional abilities of Grun1 mice have not yet been studied.121

Hyperactivity improved by high-dose methylphenidate. Whereas in control mice c-FOS was very low in the prelimbic cortex and striatum and increased by MPH, in GRIN1Rgsc174 ⁄ + mice c-FOS was high in the prelimbic cortex and was reduced by MPH (at very high doses). Grin1Rgsc174 ⁄ + mice further showed increased phosphorylation of the protein ERK2 in the nucleus accumbens, which hardly changed even after a very extreme MPH dose (30 mg/kg). The authors concluded that the behavioral symptoms of the GRUN1 mouse were due to NMDA receptor dysfunction in the relevant brain regions, and that the effect of MPH in the GRIN1 mouse was not mediated specifically via the DAT but via other receptors or influences, since the DAT should have already shown effects at much lower doses.122 The authors further point out that glutamatergic neurotransmission is also altered in SHR. SHR do not respond at all to MPH with respect to hyperactivity, but do respond to AMP (see there).

3.5. AGCYAP1-KO mouse

The Adcyap1 gene encodes the pituitary-generated neuropeptide adenylate cyclase activating polypeptide 1. Mice lacking the ADXAP1 gene (Adcyap1(-/-)) show increased novelty seeking and hyperactivity. One study found sensory-motor gating deficits in them in the form of prepulse inhibition (PPI) deficits. Amphetamine was able to normalize PPI and hyperactivity. This occurred via serotonin 1A (5-HT(1A)) receptor signaling. Wild-type mice also developed hyperactivity in response to the 5-HT(1A) agonist 8-hydroxy-2-(di-n-propylamino)tetralin, which could likewise be relieved by AMP. AMP-treated AGCYAP1-KO mice were also found to have increased c-Fos-positive neurons in the PFC, suggesting increased inhibitory control by prefrontal neurons.100

3.6. More ADHD mouse/rat models

Other rodent models of ADHD that we have not previously described include:123

  • Prenatal Alcohol Exposure Rat
  • Prenatal Nicotine Exposure Rat / Mouse
  • Neurokinin-1 Receptor Knockout Mouse

3.9. Drosophila (fruit fly)

Research on Drosophila showed that gene variants determined the behavior of Drosophila to, for example, unpleasant air blasts.
Drosophila that showed a hyperactive response to air blasts for a particularly long time had a specific mutation of the dopamine transporter gene, which is one of the most important candidate genes in ADHD.124 When these Drosophila were treated with cocaine, they quieted down more quickly.
The dopamine D1 receptor was essential for learning behavior in Drosophila. Drosophila with an artificially silenced D1 receptor (throughout the brain) could not learn that a particular odor acted as a warning signal for an air blast.125
If the D1 receptor gene was repaired exclusively in the brain region of the “Central Complex”, the Drosophila were no longer hyperactive, but were still unable to learn. If, on the other hand, the D1 receptor gene was repaired only in the brain region of the “mushroom body”, the ability to learn was restored, while the hyperactivity remained.124

A Drosophila breeding line that was also bred toward (in)sleep problems simultaneously showed considerable hyperactivity and increased sensitivity to environmental stimuli after 60 generations.126

4. Animal models that inadequately represent ADHD

There are quite a few other animal models that show symptoms of ADHD. However, many of them have only single symptoms or are not suitable to describe the etiology of ADH)S for other reasons:41127

4.1. Naples high-excitability rat (NHE)

  • Hyperactive in new environment
  • Not hyperactive or impulsive in familiar surroundings
  • No permanent attention problems

4.2. WKHA advice

  • Hyperactive
  • Not impulsive
  • No problems with sustained attention

4.3. Acallosal mouse

  • Hyperactivity
    • Becomes hyperactive only with age
  • Impulsive
    • Impulsivity decreases with the number of tests on this; this does not correspond to ADHD
  • Impairment in conditioned learning tasks

4.4. Hyposexual advice

4.5. PCB-exposed rat

  • Hyperactivity
  • No permanent attention problems

4.6. Lead-exposed mouse

  • Hyperactivity
  • Ataxia
  • Other symptoms of lead poisoning well distinguishable from ADHD

4.7. Rat reared in social isolation

  • Hyperactivity in new environment
  • Increased omission errors
  • Endurance problems
  • No impulsivity
  • No impairment in the 5-choice serial reaction time (5-CSRT) sustained attention test task acquisition measure

4.8. TAAR-1-KO mouse

  • Reduced prepulse inhibition128
  • Unchanged:128
    • Weight, height, body temperature
    • Anxiety Behavior
    • Stress Responses
  • Amphetamine administration128
    • Has a stronger psychomotor stimulating effect
    • Increased increase in dopamine and norepinephrine in the dorsal striatum
    • Correlates with 262% increase in high-affinity D2 receptors (D2-high) in the striatum (48.5% D2-high receptors in the stratum compared to 18.5% in normal mice)

4.9. MACROD1 and MACROD2-KO mice

  • (Female only) MACROD1-KO mice showed motor coordination problems.129
  • MACROD2-KO mice show hyperactivity, which further increased with age, in combination with a bradykinetic gait pattern (slower and shuffling gait, as in Parkinson’s disease)129

4.10. Stroke-prone spontaneously hypertensive rat (SHRSP/Ezo)

The stroke-prone spontaneously hypertensive rat (SHRSP/Ezo) showed in one study130

  • a reduced D-serine/D-serine + L-serine ratio in the mPFC and the hippocampus
    • D-serine binds to NMDA receptors
  • D-amino acid oxidase (DAAO, a D-serine-degrading enzyme) was increased in mPFC
  • Serine racemase (SR, D-serine biosynthetic enzyme) was decreased in the hippocampus
  • a microinjection of a DAAO inhibitor
    • in the mPFC increased the DL ratio and decreased ADHD symptoms such as inattention and hyperactivity in the Y-maze test
    • into the hippocampus also increased the DL ratio, but did not change ADHD symptoms

The authors conclude NMDA receptor dysfunction in the mPFC as the cause of ADHD symptoms in SHRSP/zo

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