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ADHD animal models with reduced extracellular dopamine

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ADHD animal models with reduced extracellular dopamine

In this paper, we collect animal models of ADHD that exhibit reduced extracellular dopamine levels.
Animal models in which we only know that dopamine is reduced, without knowing whether extracellular or phasic, have also been included here for the time being.
If we have only shot at a reduced extracellular dopamine level due to increased DAT, this is characterized.

1. Animal models for ADHD with reduced extracellular dopamine levels

1.1. Spontaneous(ly) hypertensive rat (SHR) (DAT increased = DA extracellular decreased, phasic decreased)

The SHR is the most important animal model for researching ADHD.12

The spontaneous(ly) hypertensive rat (SHR) was initially bred from 1963 as an animal model for high blood pressure.3 The animals have genes that cause them (without early childhood stress experience) to suffer increasing blood pressure with age, which reaches the level of hypertension from around day 28 and is accompanied by hyperactivity.4
SHR was developed by mating Wistar Kyoto males with markedly elevated blood pressure to females with slightly elevated blood pressure. Subsequently, brothers were mated with sisters, with continued selection for spontaneous hypertension.5
in 1992, it was established that SHRs are also a model of ADHD-HI.6 Since then, the SHR have served as a scientific animal model for ADHD-HI (with hyperactivity) in ADHD research.
Although dopamine influences cortical blood flow, high blood pressure is not a symptom of ADHD.7 This makes it clear that SHR only represents one of many different ADHD models and by no means universally represents ADHD.

By crossing the SHR with WKY strains, a hyperactive and stress-sensitive but less aggressive and non-hypertensive strain (WK/HA) and a hypertensive but non-hyperactive strain (WK/HT) could be further bred. Compared to WKY, MK/HA exhibit changes in monoamine function, particularly in the noradrenaline and dopamine uptake of the PFC. In addition, the neuroendocrine reactions in the HPA axis and POMC peptides in the anterior and posterior pituitary are altered.8910 However, WK/HA is rarely used in studies.

Hypertension in SHR could be a risk factor that in turn could cause cognitive symptoms independently of hyperactivity. High blood pressure increases the risk of senile dementia and Alzheimer’s disease.1112
Four- to five-week-old SHR do not exhibit hypertension, but many studies are conducted on SHR at this age, and ADHD-related symptoms persist when hypertension occurs. It is not clear whether or not late-onset hypertension is a problem in this model.
Comparative studies including WK/HT indicate that the ADHD-relevant symptoms of SHR are not caused by elevated blood pressure.13
The increased blood pressure of the SHR appears to be a consequence of a disorder of the nigrostriatal dopaminergic system. In vitro, lower releases of phasic dopamine in the caudate nucleus were seen in SHR compared to Wistar-Kyoto rats (WKY). In vivo, extracellular (“tonic”) dopamine and the metabolite DOPAC were also lower in the caudate nucleus of SHR than in WKY. Bilateral lesions of the pars compacta of the substantia nigra of 4-week-old SHR and WKY significantly attenuated the development of hypertension in SHR, with no effect on heart rate. The DOPAC/dopamine ratio and the HVA/dopamine ratio were lower in non-lesioned SHR than in non-lesioned WKY, indicating lower dopamine turnover in SHR. Six weeks after the lesion, dopamine concentrations in the caudate nucleus were reduced in both SHR and WKY. At this time point, stimulus-driven (phasic) dopamine release from the remaining terminals was significantly increased in caudate nucleus slices of SHR, but not in WKY. This normalization of dopaminergic activity may be the causative factor for the attenuation of the development of hypertension in SHR after bilateral lesion of the pars compacta of the substantia nigra.14

It is unlikely that all specimens exhibit identical behavior that stresses young animals to exactly the same extent. Nevertheless, the pathological behavioral patterns are present in all specimens.15 This shows that certain genetic constellations can cause mental disorders even without additional stressful environmental influences, i.e. that the genes + environment formula is a common but not exclusive etiological model for mental disorders.
Interestingly, the first generations of SHR had a massive problem with cannibalism of newborns. This problem is now solved by keeping the pregnant rat mothers in isolation until the young reach a certain age. It would be interesting to find out whether the SHR also exhibits special behavior towards young animals in other ways.

The importance of SHR as an ADHD model should be properly appreciated. Just as in humans there should be little doubt that there are many different ADHD pathways (hundreds, if not thousands of genes are involved, which can act in very different ways in different individuals), the SHR is not the only model animal for ADHD and here ADHD-C. The SHR can therefore at best represent 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 possible combinations. Certainly not all candidate genes have the same influence and the same frequency, but the line of thought shows that SHR can only be one of many possible genetic constellations of ADHD.

1.1.1. ADHD-relevant behaviors of the SHR

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

1.1.1.1. Hyperactivity
  • Hyperactivity16
    • Only develops with age
    • Improved by MPH and AMP7
    • Improved by guanfacine17
    • Improved by atomoxetine18
    • Improved by administration of dexmedetomidine for several days (25 μg/kg)19
    • Hyperactivity present7
      • Only in comparison to WKY rats
      • WKY are hyperactive in the first 15 minutes in an unfamiliar environment, SHR even beyond that20
      • In tests such as the living eight labyrinth
      • Overactive in operant discrimination tests compared to WKY rats.
    • No hyperactivity
      • In familiar environments
      • Less active than Sprague-Dawley rats in open field tests21
      • Less active in running wheels than WKY rats21
      • Less active than Sprague-Dawley and Wistar rats in both the outdoor and home cage tests22
1.1.1.2. Impulsiveness
  • Impulsiveness16
    • Impaired ability to hold back reactions16
    • Develops with age
    • Improved by MPH and AMP7
    • Improved by guanfacine17
  • Choice impulsivity (preference for immediate small rewards over delayed larger rewards)23
1.1.1.3. Inattention
  • Inattention16
    • Improved by MPH
    • Improved by guanfacine17
1.1.1.4. Spatial working memory impaired

SHR show deficits in spatial working memory242513

  • improved by choline and uridine administration26
  • improved by dexmedetomidine19
1.1.1.5. Delay-dependent working memory deficits

SHR showed delay-dependent working memory deficits that were similar, albeit less severe, to those of rats with hippocampal lesions27

1.1.1.6. Time processing problems

Female SHR showed impairments in the processing of elapsed time, especially in the discrimination of longer time spans.27

1.1.1.7. Targeted behavior impaired
  • Targeted behavior impaired
    • Restored by MPH28
1.1.1.8. Performance stability reduced
  • Low power stability16
1.1.1.9. Increased sensitivity to stress
  • Increased reactions to stress29
  • With increasing age and in parallel with increasing high blood pressure, SHR is observed to have an increasing sensitivity of the HPA axis to stress.30
    High blood pressure is an organic consequence of chronic stress.31
1.1.1.10. Emotional symptoms (?)

There are indications of altered emotional communication and reaction in SHR.
Rats communicate their emotional state via ultrasonic vocalizations (USV). 22 kHz represent aversive reactions, 50 kHz represent appetitive reactions.
After fear conditioning, SHR emitted more short 22-kHz and less 50-kHz USV overall. In addition, SHR emitted less long 22-kHz USV than Wistar rats. SHR showed no increase in heart rate (HR) on 50 kHz playback, but a sharp decrease in HR on 22 kHz playback. These phenomena in SHR may represent deficits in emotional perception and processing that also occur in ADHD sufferers.32

1.1.1.11. Subtypes corresponding to ADHD-HI and ADHD-I

One study found subgroups of SHR that differed significantly in terms of impulsivity. Impulsive SHRs showed significantly different behavioral subgroups compared to non-impulsive SHRs and WKYs (as controls, with the WKYs showing no behavioral subgroups):33

  • 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 the PFC
    • Acute administration of a cannabinoid agonist reduced impulsivity in impulsive SHR, without change in WKY

As SHR is not a matter of gene-identical, cloned animals, but a strain bred for specific symptoms, whose individual animals therefore 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 levels in ADHD-HI / ADHD-C subtypes of SHR seem to contradict Woodman’s findings:

  • Aggression and outwardly directed anger correlated with increased noradrenaline in Woodman34
  • In Woodman, however, anxiety correlated with increased adrenaline34

1.1.2. Effect of medication on symptoms of SHR

1.1.2.1 Effect of MPH on SHR

SHR react to MPH:

  • Increased attention and memory performance35
  • Dose-dependent reduced impulsivity35
  • Hyperactivity;
    • Unchanged at low and medium doses35
    • Increased at high doses35
    • Reduced at very high doses6
  • Goal-oriented behavior restored by MPH28

Contrary to the view of the authors of the meta-study, we see no reason to question the SHR as a model for ADHD-HI. Since ADHD is multifactorial and SHR are merely an animal model bred for specific symptoms, SHR can only represent one variant of ADHD (which, moreover, corresponds more closely to ADHD-HI than ADHD-I). This also means that the effects of 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.36

Serotonin transporters in the striatum were not altered by MPH, even with long-term administration.37

1.1.2.2. Effect of amphetamine medication on SHR

Amphetamine medication caused a reduction in hyperactivity in SHR.6

1.1.2.3. Effect of atomoxetine on SHR

Atomoxetine caused a reduction in hyperactivity.18

1.1.3. Dopamine system impaired

The data indicate a hypodopaminergic function in the SHR model.7

1.1.3.1. Dopamine synthesis impaired

Tyrosine hydroxylase is reduced.

In SHR, the miRNA let-7d is said to be overexpressed in the PFC and the expression of galectin-3 is reduced, which leads to a downregulation of tyrosine hydroxylase, which is a precursor of dopamine synthesis.38 This results in an impairment of dopamine synthesis. However, one study found excessive galectin-3 blood plasma levels in children with ADHD.39
Dopamine is synthesized in the brain in two steps. First, the amino acid tyrosine is catalyzed by the enzyme tyrosine hydroxylase into l-3,4-dihydroxyphenylalanine (L-DOPA), then L-DOPA is decarboxylated to produce dopamine.
On day P5 and P7 (5 and 7 days after birth, respectively), tyrosine hydroxylase gene expression was found to be reduced.40
Reduced tyrosine hydroxylase expression in neostriatum and nucleus accumbens, with identical levels of dopamine and the dopamine metabolites in the striatum of SHR and control rats.7

Furthermore, dopamine uptake in the striatum was significantly reduced in SHR in the first month of life.40

SHR showed a weaker release of dopamine and acetylcholine in the striatum in response to glutamate.41

1.1.3.2. DAT reduced in the first few weeks, increased in adult SHR

The reports on DAT expression in SHR are inconsistent.

  • Reduced in the first month of life, normalized later42
  • Decreases in the midbrain on day P27 to P4940
  • Increased over the entire lifetime43
  • Overexpressed in adult SHR40

Surprisingly, the dopamine reuptake inhibitor nomifensine increases dopamine release to the same extent in SHR and WKY in the nucleus accumbens and caudate-putamen. This would be expected to be different with an increased tonic dopamine level in SHR.7

1.1.3.3. D1 receptor expression increased

The majority of studies confirm increased DRD1 and DRD-2 expression in SHR in the nucleus accumbens, striatum and PFC. Some studies found no differences in the expression of DRD1 and DRD2. The higher expression of DRD1 and DRD2 is consistent with reduced dopamine release causing upregulation of the receptors.7

Consistent with the later decline in stimulus-elicited dopamine, postsynaptic DRD1 levels are elevated in the caudate-putamen and nucleus accumbens in SHR, consistent with a role for dopamine in ADHD.4443

1.1.3.4. D2 receptor expression 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.18454647
Other studies did not find increased D2 expression in SHR40 compared to WYK rats.42

Postsynaptic D1/D2-like receptors appear to be less sensitive in SHR, while presynaptic dopamine D2-like autoreceptors, which are mainly found in the nucleus accumbens, are probably more sensitive.48

Increased DRD2 expression may be a compensatory mechanism for low DAT function during early development in SHR. The net effect of such changes has been hypothesized to result in increased extracellular dopamine levels during the pre-withdrawal period in SHR (Russell, 2000), which later transitions to dopamine hypofunction.

1.1.3.5. D3 receptor expression unchanged

The previous studies found the DRD3 receptor unchanged in SHR7

1.1.3.6. D4 receptor expression in the PFC reduced (?)

SHR showed significantly reduced dopamine D4 receptor gene expression and protein synthesis in the PFC. Other dopaminergic genes in the midbrain, PFC, temporal cortex, striatum or amygdala of SHR were unchanged compared to WKY.49
Mill found no change in D4 receptor expression compared to WYK rats.42

1.1.3.7. Extracellular (tonic) dopamine altered?

Several studies found a reduced basal extracellular dopamine concentration in the caudate nucleus and nucleus accumbens at 8-9 weeks of age.451450
One study found increased extracellular tonic dopamine release in the shell of the nucleus accumbens.29
Some studies found no differences in extracellular dopamine concentrations.5152

1.1.3.8. Phasic dopamine release reduced

In SHR, the dopaminergic presynapses of the mesocortical, mesolimbic and nigrostriatal neurons appear to release less phasic dopamine in response to electrical stimulation/depolarization due to high extracellular K+ concentrations.53
SHR/NCrl showed reduced KCl-evoked dopamine release in the dorsal striatum compared to WKY/NCrl (an ADHD-I model).54

1.1.3.9. Accelerated dopamine uptake in the striatum

SHR/NCrl showed faster dopamine uptake in the ventral striatum and nucleus accumbens than controls, while WKY/NCrl (an ADHD-I model) showed faster dopamine uptake only in the nucleus accumbens.54 This is consistent with increased DAT activity in SHR.

The striatal and mesolimbic dopaminergic neurotransmission of the SHR is excessive (which explains the hyperactivity of the SHR), while the basal efflux of noradrenaline in the PFC is attenuated.55

1.1.3.10. Mesocortical dopamine system unchanged

No changes in the mesocortical dopaminergic system were found in juvenile SHR:56

  • no change in the area density of TH-immunoreactive (TH-ir) dopaminergic neurons in the VTA
  • no changes in the volume density of TH-ir fibers in layer I of the prelimbic subregion of the mPFC
  • no changes in the percentage of dopaminergic TH-ir fibers in layer I of the PrL subregion of the mPFC
1.1.3.11. Reaction to MPH / AMP

Stimulation of dopamine release by MPH or AMP in the nucleus cumbens shell caused a greater increase in dopamine in SHR than in WKY. Increasing KCl stimulation in the nucleus cumbens shell reversed this differential increase (greater increase in extracellular dopamine release in WKY than in SHR).29 This suggests that in SHR, a higher dopamine tone in the nucleus cumbens shell in combination with lower intracellular dopamine reserves contributes to the increased activity compared to WKY.7

1.1.4. Adenosine system altered in SHR

The adenosine system interacts with the dopamine system.
In SHR, adenosine in blood plasma57 and the amount of adenosine A2A receptors in frontocortical nerve terminals (presynapses) is increased.58 The bioavailability of adenosine in vascular tissues and in arteries of SHR appears to be increased, while at the same time adenosine transporters (ENT) and A1 and A2A receptors are downregulated. In veins, the expression of ARs and ENTs appears to be unchanged, while the A2A receptor appears to be upregulated and the ENT2 transporter appears to be downregulated.59

Adenosine receptor antagonists improve various ADHD symptoms in SHR

  • Caffeine (non-selective A1 and A2A adenosine receptor antagonist)
    • Object recognition60
    • social recognition61
    • spatial learning62
    • no influence on high blood pressure62
  • DPCPX (8-cyclopenthyl-1,3-dipropylxanthine, A1 antagonist)
    • Object recognition60
    • no influence on high blood pressure62
  • 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 recognition60
    • social recognition61
    • no influence on high blood pressure62

Chronic caffeine input58

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

Chronic administration of caffeine or MPH before puberty later improved object recognition in adult SHR, while the same treatment worsened it in adult Wistar rats63

There is evidence of an interaction between the cannabinoid and adenosine systems in relation to impulsive behavior in SHR:64

  • WIN55212-2 (cannabinoid receptor agonist) increased impulsive behavior
  • acute pre-treatment with caffeine canceled this out
  • chronic caffeine intake increased impulsivity

In SHR, the adenosine-mediated presynaptic inhibition of adrenergic transmission appears to be genetically reduced.65
The A1 agonist CPA increased the binding of the alpha2-adrenoceptor in the nucleus tractus solitarius in SHR about 10 times as much as in WKY.66

Adenosine influences blood pressure.67 Adenosine reduced blood pressure even more in SHR than in WKY. Adenosine reduced the heart rate in SHR and increased it in WKY68

1.1.5. Increased release of noradrenaline

In the laboratory, PFC brain cells of the SHR showed an increased release of noradrenaline in response to glutamate. This effect was not mediated by NMDA receptors, as NMDA did not alter noradrenaline release. It is hypothesized that the noradrenergic system in the PFC of SHR is overactivated69 or dysregulated, possibly in the form of higher alpha-adrenoceptor sensitivity.20 The A1 agonist CPA increased the binding of the alpha2-adrenoceptor in the nucleus tractus solitarius in SHR about 10 times more than in WKY66
In SHR, the adenosine-mediated presynaptic inhibition of adrenergic transmission appears to be genetically reduced.70

In SHR, autoreceptor-mediated inhibition of noradrenaline release appears to be further 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.5371

1.1.6. Serotonin for SHR

SHR show an increased number of serotonin transporters in the striatum in adulthood, which remained unchanged by MPH.37

1.1.7. GABA for SHR

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

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

whereas this was not the case with Wistar rats (which are not an ADHD animal model).72

One study found evidence that the extracellular concentration of GABA may be reduced in the SHR hippocampus. An underlying defect in GABA function could be the cause of the catecholamine transmission dysfunction observed in the SHR and underlie their ADHD-like behavior.73

The GABA antagonist oroxylin A appears to improve ADHD-like behaviors in SHR via enhancement of dopaminergic neurotransmission and not via modulation of the GABA pathway as previously reported.74

1.1.8. Vitamin D3 metabolism altered in SHR

In SHR, the activity of 25-hydroxyvitamin D-1-alpha-hydroxylase appears to be reduced. This could be due to impaired renal metabolism or responsiveness to cyclic adenosine 3’,5’-monophosphate. In both SHR and WKY, a one-week restriction of dietary phosphorus led to an increase in plasma D3 concentration. This did not result in a change in blood pressure.75 Another study found both increased and decreased D3 levels.76

1.1.9. Stress systems changed

1.1.9.1. Over-intense HPA axis stress response in SHR compared to WKY

7-week-old SHR show significant differences compared to WKY of the same age77

  • Increased corticosterone responses to bleeding and ether stress
    Note: Since SHR represent a model for ADHD-HI and not ADHD-I, we would expect flattened stress corticosterone responses as found in other studies78
  • Elevated basal corticosterone levels
    Note: Reduced basal cortisol levels are usually found in people with ADHD regardless of subtype
  • Reduced plasma ACTH responses to bleeding and ether stress
  • Lower plasma ACTH responses to iv CRH injection
  • Identical plasma ACTH responses to vasopressin
  • Lower CRH concentrations in the hypothalamus (median eminence), posterior lobe of the pituitary gland and cerebral cortex
  • Reduced CRH release from the hypothalamus
  • Identical CRH response to 56 mM KC1

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

  • The ACTH response to stress is identical
  • The CRH concentrations in the hypothalamus (median eminence) are identical
  • Prevent the development of high blood pressure in SHR

Corticosterone given as a substitute restored the increase in blood pressure in SHR.

Dexamethasone as a glucocorticoid receptor (GR) agonist improved ADHD-HI symptoms in SHR.79 A GR antagonist (mifepristone) elicited ADHD-HI symptoms in other rat species (not otherwise showing ADHD symptoms).80
Dexamethasone (as a GR agonist) increased the previously (compared to WKY) reduced serotonin level in the PFC of SHR and improved attention deficit and hyperactivity. In contrast, a GR inhibitor (RU486) increased inattention and hyperactivity. Dexamethasone increased the expression of 5-HT and 5-HT2AR in the PFC and decreased the expression of 5-HT1AR. In contrast, RU486 decreased the expression of 5-HT and 5-HT2AR and increased the expression of 5-HT1AR.81

These results indicate this:

  • HPA axis overactivated in young SHR
  • Reduced ACTH response to stress and CRH due to higher corticosterone levels in plasma
  • Glucocorticoids are essential for the development of hypertension in SHR
  • In ADHD-HI / ADHD-C (with hyperactivity), the GR receptor may be addressed too weakly, whether due to an insufficient number or sensitivity of GR or an excessive number of MR
  • In SHR, the glucocorticoid system is closely linked to the serotonin system

Other studies have observed significantly reduced basal levels of15

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

SHR have genetically determined excessive expression of mineralocorticoid receptors (MR) and normal expression of glucocorticoid receptors (GR).82
A shift in the balance between MR and GR in the direction of increased MR therefore 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) triggered ADHD-HI symptoms in other rat species (which otherwise do not show ADHD symptoms).80

This is consistent with our view that ADHD-HI (with hyperactivity) is caused or driven 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 business of cortisol. GR, on the other hand, are only addressed when cortisol levels are very high and have the function of switching off the HPA axis again. In the case of MR overload and a reduced cortisol stress response (as is typical for ADHD-HI), the unoccupied MR absorb the cortisol so that the GR are not sufficiently occupied to trigger the HPA axis shutdown.
If, on the other hand, the MR are underrepresented or the cortisol stress response is excessive (as in ADHD-I), the GR are addressed too quickly and the HPA axis is switched off too frequently.

1.1.9.3. MiRNA expression in SHR alters glucocorticoid receptor

For the miRNA

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

significantly reduced expression was found in the ADHD rat model of SHR, which was associated with promoter inhibition activity of the glucocorticoid receptor Nr3c1.83

SHR, corticosterone and stress sensitivity

Castrated or sterilized SHR showed a reduced blood pressure and an increased basal corticosterone level,84 which in our opinion could indicate, contrary to the authors’ conclusion, that a too low basal corticosterone level (and a too low response intensity of the HPA axis) could cause the hypertension. In addition, the link 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 four to five times higher urinary excretion of 6β- [3H] OH-corticosterone than control Wistar-Kyoto rats, consistently before and after the development of hypertension.
Hypertension as well as 6-beta-hydroxylation could be inhibited by selective 3A P-450 cytochrome inhibitors.8586

SHR react much more sensitively to heat or other stressors,87 which correlates with the increased sensitivity that exists in ADHD.

1.1.10. SHR and the immune system

1.1.10.1. Young SHR

Young SHR show in comparison to WKY88

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

Older SHR show in comparison to WKY88

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

In the animal model of ADHD-HI (with hyperactivity), the Spontaneous(ly) hypertensive rat (SHR) found in the brain regions (not in the peripheral blood) of adult male animals:89

  • Increased levels of reactive oxygen species (ROS) in the cortex, striatum and hippocampus
  • Reduced glutathione peroxidase activity in the PFC and hippocampus
  • Reduced TNF-α levels in the PFC, the rest of the cortex, hippocampus and striatum
  • Reduced IL-1β levels in the cortex
  • Reduced IL-10 levels in the cortex
1.1.10.4. Gut-brain axis in SHR

Treatment with dexmedetomidine19

  • changed the composition of the intestinal microbiota. Dexmedetomidine increased:
    • Ruminiclostridium
    • Jeotgalicoccus
    • Corynebacterium_1
    • Ruminococcaceae_UCG_010
    • Butyricimonas
    • Parasutterella
    • unclassified_Muribaculaceae
  • promoted the enrichment of beneficial intestinal bacterial genera associated with anti-inflammatory effects in SHR
  • significantly improved intestinal permeability and inflammation levels in the gut and brain
  • Fecal microbiome transplantation from SHR treated with dexmedetomidine to untreated SHR caused the latter to mimic the therapeutic effects of DEX administration (hyperactivity improved, spatial working memory improved, theta EEG rhythms improved)
1.1.10.5. Taurine improved inflammatory markers and hyperactivity and reduced DAT in SHR

SHR treated with taurine showed reduced serum levels of C-reactive protein (CRP) and IL-1β.90 While low doses of taurine increased motor activity, high doses of taurine decreased it.

A study on rats came to the conclusion that taurine can have positive effects on ADHD.91

  • Low dew rates increased
    • The DAT in the striatum significantly (only) in WKY rats
    • Dopamine uptake in the striatum in both SHR and WKY rats.
  • High-dose taurine reduces (only) in SHR rats
    • The DAT in the striatum significantly
      • DAT in the striatum are increased in ADHD
    • Dopamine uptake in the striatum
      • Dopamine (re)uptake in the striatum is increased in ADHD
    • Interleukin (IL)-1β and C-reactive protein
    • The horizontal movement
    • The functional connectivity of the hippocampus (also in WKY)
    • The mean amplitude of low-frequency fluctuations (0.01-0.08 Hz) (mALFF, mean amplitude of low-frequency fluctuation (mean ALFF)) in the hippocampus on both sides (also in WKY)
  • Both low and high taurine levels increase
    • Significantly increased BDNF levels in the striatum of both SHR and WKY rats
      BDNF is reduced in ADHD

High-dose taurine reduced hyperactivity in SHR rats by decreasing inflammatory cytokines and modulating functional brain signaling:92
WKY with high dew yield

  • CRP (C-reactive protein) significantly reduced in serum
    SHR with low or high dew content
  • Interleukin (IL)-1β significantly reduced
  • CRP significantly reduced
    WKY and SHR with low dew point
  • horizontal locomotion significantly increased
    SHR with high dew point
  • horizontal locomotion significantly reduced compared to SHR control group
    WKY like SHR with high dew point
  • functional connectivity (FC) significantly reduced
  • mean amplitude of the low-frequency fluctuation (mALFF) in the bilateral hippocampus significantly reduced
    SHR with low or high dew content
  • mALFF significantly reduced compared to SHR control group

1.1.11. Cholesterol metabolism in PFC altered by SHR; MPH revises change

One study found 12 altered metabolic metabolites in the PFC in SHR (compared to WKY). The deviations of 7 of these were equalized by MPH:93

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

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

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

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

In SHR, compared with WKY rats, there were

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

These deviations 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)
    • Pro-inflammatory associated cytokines
    • NADPH oxidase subunit
  • Elevated levels of reactive oxygen species
  • Activation of microglia

and with

  • Increased noradrenaline levels in the blood plasma.

These phenomena were eliminated by an infusion of 40 ng calcitriol daily.94

40 ng calcitriol corresponds to 0.04 micrograms of vitamin D3. At a weight of approx. 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 under 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 recommended daily dose for humans. With such a dosage, considerable health risks would have to be expected in humans.

1.1.13. Brain regions reduced in size

The SHR shows various reduced brain regions

  • Vermis cerebelli significantly reduced in size49
  • Caudate nucleus significantly reduced in size49
  • Putamen significantly reduced in size49
  • PFC smaller than for WKY rats95
  • Hippocampus smaller than in WKY rats9596
  • increased ventricular volume at 3 months of age compared to WKY rats95
  • fewer neurons than in WKY rats96

The brain volume in the PFC and other regions is also reduced in ADHD.

1.1.14. Brain connectivity impaired both locally and over a wide area

With functional ultrasound imaging, which allows rapid measurement of cerebral blood volume (CBV), SHR:97

  • increased response to visual stimulation in the 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
        • reduced in the secondary cingulate cortex, the superior colliculi and the pretectal area

1.1.15. PFC neurons altered

PFC neurons of the SHR showed fewer neurite branches, a shorter maximum neurite length and less axonal growth than PFC neurons of the WKY.
The adenosine antagonist caffeine restored neurite branching and elongation in SHR neurons via PKA and PI3K signaling.
The A2A agonist CGS 21680 improved neurite branching via PKA signaling.
The selective A2A antagonist SCH 58261 restored axonal growth of SHR neurons via PI3K- alone (not through PKA signaling)98

1.1.16. Monosodium glutamate influences aggression depending on the vagus nerve

SHR were given monosodium glutamate (glutamate as a flavor enhancer) during the development phase (from day 25 for 5 weeks). This resulted in reduced aggressive behavior. Anxiety behavior remained unchanged. However, if the vagus nerve of the SHR was cut beforehand (vagotomy), monosodium glutamate did not reduce aggression, which indicates that the effect of monosodium glutamate on aggression is mediated by the gut-brain axis.99

1.1.17. θ-Rhythms of the electroencephalogram (EEG)

Dexmedetomidine significantly decreased the θ/α ratio and the θ/β ratio in SHR.19

1.1.18. Ketogenic diet

One study reported a slight improvement in ADHD symptoms with SHR, probably due to influences on the gut-brain axis. However, the improvement was much weaker than that of MPH.100

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

The stroke-prone spontaneously hypertensive rat (SHRSP/Ezo) showed in a study101

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

The authors conclude that NMDA receptor dysfunction in the mPFC is the cause of ADHD symptoms in SHRSP/Ezo.

1.3. WKY/NCrl (DAT increased = extracellular DA decreased)

WKY/NCrl represent an animal model for the ADHD-I subtype (attention deficit without hyperactivity).10210336

1.3.1. Increased tyrosine hydroxylase in WKY/NCrl

WKY/NCrl show increased tyrosine hydroxylase gene expression as adult animals.36

1.3.2. Increased DAT in adulthood from WKY/NCrl

WKY/NCrl and SHR/NCrl (ADHD-C model) show DAT gene expression on day P25. It was not quite as strongly increased in the WKY/NCrl as in the SHR/NCrl. A two-week treatment with MPH reduced DAT, although the reduction was weaker than in SHR/NCrl, especially before puberty.36

From the increased DAT we conclude that extracellular dopamine is reduced.

1.3.3. Increased dopamine uptake in the nucleus accumbens

While WKY/NCrl (an ADHD-I model) showed faster dopamine uptake than controls only in the nucleus accumbens, SHR/NCrl showed faster dopamine uptake in the nucleus accumbens and ventral striatum.54

1.3.4. Dopamine release in the striatum unchanged

Unlike SHR/NCrl, WKY/NCrl did not show reduced KCl-evoked dopamine release in the dorsal striatum compared to WKY/NHsd controls.54

1.4. SNAP-25 KO Coloboma mice (CM) (dopamine decreased, noradrenaline increased)

The Coloboma mouse mutant (Cm) serves as an animal model for research into ADHD.1271
CM show a mutation in the SNAP-25 gene and are not viable in the homozygous form, but only in the heterozygous form. Heterozygous Coloboma mice have only 50% of the normal SNAP-25 protein concentration. The relationship between SNAP-25 and ADHD is unclear. SNAP-25 is a presynaptic protein that regulates the exocytotic release of neurotransmitters (fusion of the vesicles with the cell membrane, which releases the neurotransmitter stored in the vesicles into the synaptic cleft).

Cm mice show the following symptoms:

  • Hyperactivity104105
    • With head bobbing / head circles106
    • Amphetamines reduce hyperactivity105 at low doses107
    • Methylphenidate increased hyperactivity with subcutaneous injection from 2 mg / kg to 32 mg / kg105
    • Noradrenaline depletion reduced hyperactivity108
  • Impulsiveness is questionable
  • Inattention is questionable
    • For this109
    • On the other hand71

Cm mice show compared to control mice:111

  • Changes in the HPA axis111
    • No CRH increase in the hypothalamus due to acetylcholine
    • Strongly increased corticosterone level in plasma due to movement restriction stress
  • Changes in the dopamine system
    • Tyrosine hydroxylase:112113
      • Unchanged in the VTA
      • In the substantia nigra unchanged
      • Increased in the locus coeruleus
    • Reduced release of glutamate through (K+) depolarization in cortical synaptosomes
    • DRD2 expression113
      • Increased in the VTA
      • Increased in the substantia nigra
        -> which suggests a reduced firing rate of dopamine neurons
      • Unchanged in the striatum
    • DRD1 expression
      • Unchanged in the striatum113
    • Dopamine release
      • In the striatum is reduced
        • Only reduced dorsally, not ventrally111
      • In the nucleus accumbens is reduced113
      • Dopamine metabolites DOPAC and HVA reduced in the striatum
        -> consistent with reduced dopamine release and reduced dopamine turnover114
        -> hypofunctional dopaminergic system, similar to SHR71
  • Changes in the noradrenergic system
    • Expression of α2A adrenoceptors increased in the locus coeruleus113112
    • Noradrenergic function appears to be increased
      • Noradrenaline levels increased in the striatum and nucleus accumbens113
      • Withdrawal of noradrenaline by DSP-4 reduces hyperactivity, but does not completely eliminate it108
  • Changes in the serotonergic system
    • Significantly reduced serotonin levels in the dorsal, but not in the ventral striatum111

1.5. 6-OH dopamine-lesioned mouse/rat (dopamine reduced)

6-OHDA mice are mice in which the dopaminergic cells are destroyed 5 days after birth using 6-hydroxydopamine. They are considered an ADHD model and show symptoms:71115109

  • Hyperactivity (in the open field)116
    • Initially reduced, increased with repetitions
    • Diminishing after puberty117
    • Improved by MPH118117
    • Improved by AMP117
    • Not improved by selective dopamine reuptake inhibitors119
    • Improved by selective serotonin reuptake inhibitors (citalopram, fluvoxamine)11971
    • Improved by selective noradrenaline reuptake inhibitors (desipramine, nisoxetine)11971
      • These also cause reduced dopamine uptake in noradrenergic presynapses, e.g. in
        * PFC
        * Nucleus accumbens
    • Improved by DRD4 antagonists71
      • D4R-KO mice show no hyperactivity and normal avoidance behavior when treated with 6-hydroxydopamine in contrast to the lack of inhibition in lesioned wild-type animals117
  • Attention deficit in old age
  • Impulsiveness117
    • In old age (five-choice serial reaction time task)71115109
    • Others see no impulsiveness7
  • Anxiety-like behavior (in the elevated plus maze test)
  • Antisocial behavior (in social interaction)
  • Reduced cognitive functions (problems recognizing novel objects)
  • Learning difficulties in a spatial discrimination task
    • Improved by MPH118 and AMP
  • Increased sensitivity to pain120
    • Pain sensitivity is probably mediated by α-adrenergic, β-adrenergic and D2/D3 receptors
    • Atomoxetine could reduce sensitivity to pain

Neurophysiological changes in the 6-OHDA mouse/rat:

  • Changes in the dopamine system:
    • Dopamine deficiency in the striatum and nucleus accumbens116
    • DRD4 expression increased in caudate nucleus and putamen121
      • A selective D4 antagonist reduced hyperactivity, a D4 agonist increased it121122
      • Locomotor hyperactivity correlated positively with increased D4R count in the striatum117
    • Reduction of hyperactivity through:119
      • Selective noradrenaline reuptake inhibitors
      • Methylphenidate
      • Amphetamine
    • D2 receptor expression not increased121
    • Dopamine reductions, as is typical with ADHD115109
    • Changes in cortical thickness, as is typical in ADHD115109
    • Abnormalities in the neurons of the anterior cingulate cortex, as is typical in ADHD115109
  • Changes in the serotonin system
    • Serotonin transporter123
      • Binding increased in the striatum
      • Binding unchanged in the PFC

1.6. Tal1cko mice (dopamine reduced)

Most GABAergic neurons in the dopaminergic nuclei of the midbrain are dependent on the transcription factor Tal1 for their development. Tal1 functions here as a cell fate selector gene that promotes GABAergic differentiation at the expense of alternative glutamatergic neuron identities. The brainstem nuclei harboring Tal1-dependent neurons are involved 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 only in embryonic rhombomere 1 does this lead to a failure of GABAergic neurogenesis in the brainstem.
Tal1cko mice showed:124

  • Hyperactivity
  • Increased motor impulsivity
  • Changed reaction to reward
  • Delay discounting (delay aversion)
  • Impaired learning
  • The ADHD-typical paradoxical calming reaction to pharmacologically stimulated dopamine release by amphetamine and atomoxetine
  • Developmental changes in the anterior GABAergic and glutamatergic neurons of the brainstem.
    These are involved in
    • Regulation of the dopaminergic pathways
    • Basal ganglia outpout
  • Lower body temperature
  • Lower body temperature rise during stress
  • Less nest building
  • Less grooming (breeding/care behavior)
  • Reduced levels of dopamine and dopamine metabolites in
    • Nucleus accumbens (most obvious)
    • 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

1.7. THRSP-OE mice (DAT increased = extracellular DA decreased)

A line of mice with overexpressed THRSP gene in the striatum (THRSP-OE) showed102

  • Inattention when recognizing novel objects and in the Y-maze test, but
  • no hyperactivity in the outdoor test
  • no impulsiveness in the task of cliff avoidance and deceleration restriction
  • increased expression of dopamine genes (genes for dopamine transporters, tyrosine hydroxylase and dopamine D1 and D2 receptors) in the striatum
  • Methylphenidate (5 mg/kg) improved attention and normalized the expression of dopamine-related genes in THRSP-OE mice

The THRSP-OE mice could therefore represent an animal model for ADHD-I.125

We tentatively conclude from the increased DAT gene expression that there is a deficiency of extracellular and phasic dopamine in the striatum.

THRSP-OE mice with ADHD-I traits were found to have an altered protein network involved in Wnt signaling. Compared to THRSP knockout mice (KO mice), THRSP-OE mice showed:126

  • Attention problems
  • Memory disorders
  • dysregulated Wnt signaling, which impaired cell proliferation in the dentate gyrus of the hippocampus and the expression of markers for neural stem cell (NSC) activity.
  • Enriched environment plus treadmill training improved
    • Behavioral deficits
    • Wnt signal transmission
    • NSC activity

SHR/NCrl rats (ADHD-HI, hypertension) and Wistar-Kyoto rats (WKY/NCrl) (inattention) also show increased expression of the THRSP gene102

The THRS gene is involved in the regulation of lipogenesis, particularly in the lactating mammary gland. It is important for the biosynthesis of triglycerides with medium-length fatty acid chains.

1.8. TARP γ-8-KO mice / CACNG8-KO mice (DAT increased = extracellular DA decreased)

Names:
TARP γ-8: Transmembrane α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor regulatory protein γ-8
CACNG8: Calcium Voltage-Gated Channel Auxiliary Subunit Gamma 8

The TARP γ-8 protein is a subunit of the AMPA receptor (AMPAR).

Adolescent TARP γ-8 knockout (KO) mice showed:127

  • ADHD-like behaviors:
    • Hyperactivity
    • Impulsiveness
    • States of anxiety
    • impaired cognition
    • Memory deficits
  • a dysfunction of the AMPA glutamate receptor complex in the hippocampus
  • dysregulation of dopaminergic and glutamatergic transmission in the PFC
  • MPH improved significantly
    • the most important behavioral deficits
    • the abnormal synaptosomal proteins, especially in the PFC
      • a reversal of the upregulation of Grik2
      • a reversal of the upregulation of the DAT (Slc6a3)
    • the function of the synaptic AMPAR complex through upregulation of other AMPAR auxiliary proteins in the synaptosomes of the hippocampus

In humans, there are also strong associations between SNP of TARP γ-8 genes and susceptibility to ADHD.

Due to DAT upregulation in TARP γ-8-KO mice, we assume a reduced extracellular dopamine level in these mice.

1.9. D2 autoreceptor KO mouse (autoDRD2KO mice) (DA extracellularly unchanged, phasically increased)

D2 receptors occur postsynaptically as heteroreceptors on non-dopamine neurons and presynaptically on the terminals of dopamine neurons as autoreceptors.
In D2 autoreceptor KO mice (autoDrd2KO mice), only the D2 autoreceptor located on the dopamine neurons is silenced, while the postsynaptic heteroreceptor remains unaffected.
autoDRD2KO mice show:

  • Hyperactivity in the open field and on cocaine, but not in familiar surroundings128
  • increased sensitivity to cocaine129130
  • increased dopamine synthesis and release129
  • increased motivation for food rewards129

Studies in autoDRD2KO mice showed that not only D2 autoreceptors but also D2 heteroreceptors are involved in dopamine regulation. This D2 heteroreceptor-mediated mechanism is more efficient in the dorsal striatum than in the nucleus accumbens. D2R signaling thus appears to regulate mesolimbic and nigrostriatal-mediated functions differently128

D2-null mice (D2-/-) showed131

  • normal extracellular DA levels
  • reduced DA intake
  • uninhibited DA release132
  • unchanged inhibition of dopamine release through activation of GABA-B receptors133

1.10. FOXP2HUM mice (dopamine reduced)

A substitution of two amino acids (T303N, N325S) in the FOXP2 transcription factor in mice showed134

  • reduced dopamine levels in
    • Nucleus accumbens
    • Frontal cortex
    • Cerebellum
    • Putamen caudatus
    • Globus pallidus
  • Glutamate, GABA, serotonin unchanged
  • increased dendrite length and increased synaptic plasticity of medium spiny neurons (MSN) in the striatum
  • qualitatively different ultrasound vocalizations
  • reduced exploratory behavior
  • greater caution / anxiety (stayed closer to the wall of the test field)
  • viable and reproducible
    • in contrast to FOXP2-KO mice

Since FOXP2 is not expressed in dopaminergic cells, it has an indirect effect on dopamine levels.

Animal models with reduced extracellular dopamine levels without typical ADHD symptoms

1.11. NET-KO mice (noradrenaline increased, dopamine decreased in the striatum)

Mice with a genetically deactivated noradrenaline transporter (NET-KO mice) showed

  • Noradrenaline levels increased by 55 to 75 % in PFC, hippocampus and cerebellar tissue.
  • Dopamine levels in the striatum reduced by around 20 % in the tissue and extracellular dopamine levels and dopamine metabolites reduced by 50 %.135

NET-KO mice showed

  • reduced anxiety behavior
  • reduced depression behavior
  • increased sensitivity to stimulants as an indication of increased susceptibility to addiction
  • stronger increase in motor function with D2/D3 agonists, but not with D1 agonists

Since the NET in the PFC reabsorbs slightly more dopamine than noradrenaline and thus represents one of the most important dopamine-clearing mechanisms, we assume that the dopamine level in the PFC is not reduced but rather increased. In the striatum, on the other hand, dopamine is degraded less by NET and more by DAT.


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