Dear reader of, please excuse the disruption. needs about $63500 in 2024. In 2023 we received donations of about $ 32200. Unfortunately, 99.8% of our readers do not donate. If everyone who reads this request makes a small contribution, our fundraising campaign for 2024 would be over after a few days. This donation request is displayed 23,000 times a week, but only 75 people donate. If you find useful, please take a minute and support with your donation. Thank you!

Since 01.06.2021 is supported by the non-profit ADxS e.V..

$21963 of $63500 - as of 2024-05-31
Header Image
ADHD animal models with reduced extracellular dopamine


ADHD animal models with reduced extracellular dopamine

fIn this paper, we collect animal models of ADHD that exhibit decreased 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)

SHR is the most important animal model for research into 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. Consequences were that 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 an ADHD symptom.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 suggest that the ADHD-related 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 has since been 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 can barely be any doubt that there are many different ADHD pathways (hundreds, if not thousands of genes are involved, which can act in very different ways in persons with ADHD), 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): 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 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 Inattention
  • Inattention16
    • Improved by MPH
    • Improved by guanfacine17 Spatial working memory impaired

SHR show deficits in spatial working memory242513

  • improved by choline and uridine administration26
  • improved by dexmedetomidine19 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 Time processing problems

Female SHR showed impairments in the processing of elapsed time, especially in the discrimination of longer time spans.27 Targeted behavior impaired
  • Targeted behavior impaired
    • Restored by MPH28 Performance stability reduced
  • Low power stability16 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 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 could represent deficits in emotional perception and processing, as also occur in people with ADHD.32 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 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-analysis, we see no reason to question SHR as a model for ADHD-HI. Since ADHD is multifactorial and the SHR are merely an animal model bred for specific symptoms, SHR can only represent one variant of ADHD (which, moreover, corresponds to ADHD-HI rather than ADHD-I). Consequences of this also mean that the effects of SHR cannot be transferred to all people with ADHD, 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 Effect of amphetamine medication on SHR

Amphetamine medication caused a reduction in hyperactivity in SHR.6 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 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 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 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 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. D3 receptor expression unchanged

The previous studies found the DRD3 receptor unchanged in SHR7 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 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 Phasic dopamine release reduced

In SHR, the dopaminergic presynapses of the mesocortical, mesolimbic and nigrostriatal neurons appear to release less phasic dopaminergic 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 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 Mesocortical dopamine system unchanged

No change in the mesocortical dopaminergic system was 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 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 found 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 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. 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. 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 associated with promoter inhibitory 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 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 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 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. 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. 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 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) 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. SLA16 (SHR.LEW-Anxrr16)

SLA16 (SHR.LEW-Anxrr16) is an inbred strain just like the SHR and differs from the SHR only by gene deviations on chromosome 4 (Anxrr16).101
We therefore assume that SLA 16 (like SHR) is also characterized by a reduced extracellular dopamine level.

SLA16 show:101

  • higher hyperactivity/impulsivity than SHR
  • stronger learning and memory deficits than SHR
  • a lower basal blood pressure than SHR
  • not the single nucleotide polymorphism (SNP) in the 3’UTR of the Snca gene, which is only upregulated in SHR in the hippocampus.
  • not the increase in alpha-synuclein in the hippocampus as in SHR

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

The stroke-prone spontaneously hypertensive rat (SHRSP/Ezo) showed in a study102

  • 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, converts L-serine to D-serine) 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 NMDA receptor dysfunction in the mPFC as the cause of ADHD symptoms in SHRSP/Ezo.

Pure norepinephrine reuptake inhibitors (desipramine) and mixed dopamine/norepinephrine reuptake inhibitors (MPH) improved LTP in the mPFC of SHRSP/Ezo.
MPH increased dopamine in the mPFC in WKY/Ezo more than in SHRSP/Ezo.
Pure dopamine reuptake inhibitors (GBR-12909) increased dopamine levels in the mPFC only in WKY/Ezo, but not in SHRSP/Ezo. This could be due to a pre-existing functional impairment of DAT in SHRSP/Ezo, so that DAT inhibition has no further effect. However, this is contradicted by the fact that the basal dopamine levels in the mPFC of SHRSP/Ezo are reduced.103

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

WKY/NCrl represent an animal model for the ADHD-I subtype (attention deficit without hyperactivity).10410536

1.4.1. Increased tyrosine hydroxylase in WKY/NCrl

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

1.4.2. Increased DAT in adulthood from WKY/NCrl

Both 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.

1.4.3. 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

1.4.4. 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

1.5. 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:

  • Hyperactivity106107
    • With head bobbing / head circles108
    • Amphetamines reduce hyperactivity107 at low doses109
    • Methylphenidate increased hyperactivity with subcutaneous injection from 2 mg / kg to 32 mg / kg107
    • Noradrenaline depletion reduced hyperactivity110
  • Impulsiveness is questionable
  • Inattention is questionable
    • For this111
    • On the other hand71

Cm mice show compared to control mice:113

  • Changes in the HPA axis113
    • 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:114115
      • 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 expression115
      • 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 striatum115
    • Dopamine release
      • In the striatum is reduced
        • Only reduced dorsally, not ventrally113
      • In the nucleus accumbens is reduced115
      • Dopamine metabolites DOPAC and HVA reduced in the striatum
        -> consistent with reduced dopamine release and reduced dopamine turnover116
        -> hypofunctional dopaminergic system, similar to SHR71
  • Changes in the noradrenergic system
    • Expression of α2A adrenoceptors increased in the locus coeruleus115114
    • Noradrenergic function appears to be increased
      • Noradrenaline levels increased in the striatum and nucleus accumbens115
      • Withdrawal of noradrenaline by DSP-4 reduces hyperactivity, but does not completely eliminate it110
  • Changes in the serotonergic system
    • Significantly reduced serotonin levels in the dorsal, but not in the ventral striatum113

1.6. 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:71117111

  • Hyperactivity (in the open field)118
    • Initially reduced, increased with repetitions
    • Diminishing after puberty119
    • Improved by MPH120119
    • Improved by AMP119
    • Not improved by selective dopamine reuptake inhibitors121
    • Improved by selective serotonin reuptake inhibitors (citalopram, fluvoxamine)12171
    • Improved by selective noradrenaline reuptake inhibitors (desipramine, nisoxetine)12171
      • These also cause reduced dopamine uptake in noradrenergic presynapses, including 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 animals119
  • Attention deficit in old age
  • Impulsiveness119
    • In old age (five-choice serial reaction time task)71117111
    • 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 MPH120 and AMP
  • Increased sensitivity to pain122
    • 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 accumbens118
    • DRD4 expression increased in caudate nucleus and putamen123
      • A selective D4 antagonist reduced hyperactivity, a D4 agonist increased it123124
      • Locomotor hyperactivity correlated positively with increased D4R count in the striatum119
    • Reduction of hyperactivity through:121
      • Selective noradrenaline reuptake inhibitors
      • Methylphenidate
      • Amphetamine
    • D2 receptor expression not increased123
    • Dopamine reductions, as is typical with ADHD117111
    • Changes in cortical thickness, as is typical in ADHD117111
    • Abnormalities in the neurons of the anterior cingulate cortex, as is typical in ADHD117111
  • Changes in the serotonin system
    • Serotonin transporter125
      • Binding increased in the striatum
      • Binding unchanged in the PFC

1.7. 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 this leads to a failure of GABAergic neurogenesis in the brainstem only in embryonic rhombomere 1.
Tal1cko mice showed:126

  • 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 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 the
    • 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 (DAT increased = extracellular DA decreased)

A line of mice with overexpressed THRSP gene in the striatum (THRSP-OE) showed104

  • 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.127

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:128

  • 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 gene104

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.

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

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:129

  • ADHD-like behaviors:
    • Hyperactivity
    • Impulsiveness
    • States of anxiety
    • impaired cognition
    • Memory deficits
  • a dysfunction of the AMPA glutamate receptor complex in the hippocampus
  • a 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.

1.10. 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 surroundings130
  • increased sensitivity to cocaine131132
  • increased dopamine synthesis and release131
  • increased motivation for food rewards131

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 differently130

D2-null mice (D2-/-) showed133

  • normal extracellular DA levels
  • reduced DA intake
  • uninhibited DA release134
  • unchanged inhibition of dopamine release through activation of GABA-B receptors135

1.11. FOXP2HUM mice (dopamine reduced)

A substitution of two amino acids (T303N, N325S) in the FOXP2 transcription factor in mice showed136

  • 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, this is an indirect effect on dopamine levels.

Animal models with reduced extracellular dopamine levels without typical ADHD symptoms

1.12. 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 %.137

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.

  1. Sontag, Tucha, Walitza, Lange (2010): Animal models of attention deficit/hyperactivity disorder (ADHD): a critical review. Atten Defic Hyperact Disord. 2010 Mar;2(1):1-20. doi: 10.1007/s12402-010-0019-x.

  2. Kim, Woo, Lee, Yoon (2017): Decreased Glial GABA and Tonic Inhibition in Cerebellum of Mouse Model for Attention-Deficit/Hyperactivity Disorder (ADHD). Exp Neurobiol. 2017 Aug;26(4):206-212. doi: 10.5607/en.2017.26.4.206.

  3. Charles River: Spontaneously Hypertensive (SHR) Rat Details

  4. Lee WS, Yoon BE (2023): Necessity of an Integrative Animal Model for a Comprehensive Study of Attention-Deficit/Hyperactivity Disorder. Biomedicines. 2023 Apr 24;11(5):1260. doi: 10.3390/biomedicines11051260. PMID: 37238931; PMCID: PMC10215169. REVIEW

  5. Criver: Details zur SHR

  6. Sagvolden, Metzger, Schiorbeck, Rugland, Spinnangr, Sagvolden (1992): The spontaneously hypertensive rat (SHR) as an animal model of childhood hyperactivity (ADHD): changed reactivity to reinforcers and to psychomotor stimulants; Behavioral and Neural Biology, Volume 58, Issue 2, September 1992, Pages 103-112;

  7. Regan SL, Williams MT, Vorhees CV (2022): Review of rodent models of attention deficit hyperactivity disorder. Neurosci Biobehav Rev. 2022 Jan;132:621-637. doi: 10.1016/j.neubiorev.2021.11.041. PMID: 34848247; PMCID: PMC8816876.) REVIEW

  8. Hendley (2000): WKHA rats with genetic hyperactivity and hyperreactivity to stress: a review. Neurosci Biobehav Rev. 2000 Jan;24(1):41-4. doi: 10.1016/s0149-7634(99)00050-0. PMID: 10654659.

  9. Hendley, Wessel, Van Houten (1986): Inbreeding of Wistar-Kyoto rat strain with hyperactivity but without hypertension. Behav Neural Biol. 1986 Jan;45(1):1-16. doi: 10.1016/s0163-1047(86)80001-2. PMID: 3954709.

  10. Hendley ED, Ohlsson WG (1991): Two new inbred rat strains derived from SHR: WKHA, hyperactive, and WKHT, hypertensive, rats. Am J Physiol. 1991 Aug;261(2 Pt 2):H583-9. doi: 10.1152/ajpheart.1991.261.2.H583. PMID: 1877683.

  11. Iadecola C, Gottesman RF (2019): Neurovascular and Cognitive Dysfunction in Hypertension. Circ Res. 2019 Mar 29;124(7):1025-1044. doi: 10.1161/CIRCRESAHA.118.313260. PMID: 30920929; PMCID: PMC6527115. REVIEW

  12. Novak V, Hajjar I (2010): The relationship between blood pressure and cognitive function. Nat Rev Cardiol. 2010 Dec;7(12):686-98. doi: 10.1038/nrcardio.2010.161. Epub 2010 Oct 26. PMID: 20978471; PMCID: PMC3328310. REVIEW

  13. Kantak KM, Singh T, Kerstetter KA, Dembro KA, Mutebi MM, Harvey RC, Deschepper CF, Dwoskin LP (2008): Advancing the spontaneous hypertensive rat model of attention deficit/hyperactivity disorder. Behav Neurosci. 2008 Apr;122(2):340-57. doi: 10.1037/0735-7044.122.2.340. PMID: 18410173.

  14. de Jong W, Linthorst AC, Versteeg HG (1995): The nigrostriatal dopamine system and the development of hypertension in the spontaneously hypertensive rat. Arch Mal Coeur Vaiss. 1995 Aug;88(8):1193-6. PMID: 8572872.

  15. Moll, Dale, Melby (1975): Adrenal Steroidogenesis in the Spontaneously Hypertensive Rat (SHR); Endocrinology, Volume 96, Issue 2, 1 February 1975, Pages 416–420,

  16. Russell (2002): Hypodopaminergic and hypernoradrenergic activity in prefrontal cortex slices of an animal model for attention-deficit hyperactivity disorder–the spontaneously hypertensive rat. Behav Brain Res. 2002 Mar 10;130(1-2):191-6. doi: 10.1016/s0166-4328(01)00425-9. PMID: 11864734. REVIEW

  17. Sagvolden T. The alpha-2A adrenoceptor agonist guanfacine improves sustained attention and reduces overactivity and impulsiveness in an animal model of Attention-Deficit/Hyperactivity Disorder (ADHD). Behav Brain Funct. 2006 Dec 15;2:41. doi: 10.1186/1744-9081-2-41. PMID: 17173664; PMCID: PMC1764416.

  18. Moon, Kim, Lee, Hong, Han, Bahn (2014): Effect of atomoxetine on hyperactivity in an animal model of attention-deficit/hyperactivity disorder (ADHD). PLoS One. 2014 Oct 1;9(10):e108918. doi: 10.1371/journal.pone.0108918. PMID: 25271814; PMCID: PMC4182750.

  19. Xu X, Zhuo L, Zhang L, Peng H, Lyu Y, Sun H, Zhai Y, Luo D, Wang X, Li X, Li L, Zhang Y, Ma X, Wang Q, Li Y (2023): Dexmedetomidine alleviates host ADHD-like behaviors by reshaping the gut microbiota and reducing gut-brain inflammation. Psychiatry Res. 2023 May;323:115172. doi: 10.1016/j.psychres.2023.115172. PMID: 36958092.

  20. Hellstrand K, Engel J (1980): Locomotor activity and catecholamine receptor binding in adult normotensive and spontaneously hypertensive rats. J Neural Transm. 1980;48(1):57-63. doi: 10.1007/BF01670034. PMID: 6106046.

  21. Ferguson SA, Cada AM (2003):. A longitudinal study of short- and long-term activity levels in male and female spontaneously hypertensive, Wistar-Kyoto, and Sprague-Dawley rats. Behav Neurosci. 2003 Apr;117(2):271-82. doi: 10.1037/0735-7044.117.2.271. PMID: 12708524.

  22. Sagvolden T, Pettersen MB, Larsen MC (1993): Spontaneously hypertensive rats (SHR) as a putative animal model of childhood hyperkinesis: SHR behavior compared to four other rat strains. Physiol Behav. 1993 Dec;54(6):1047-55. doi: 10.1016/0031-9384(93)90323-8. PMID: 8295939.

  23. Carbajal MS, Bounmy AJC, Harrison OB, Nolen HG, Regan SL, Williams MT, Vorhees CV, Sable HJK (2023): Impulsive choice in two different rat models of ADHD-Spontaneously hypertensive and Lphn3 knockout rats. Front Neurosci. 2023 Jan 26;17:1094218. doi: 10.3389/fnins.2023.1094218. PMID: 36777639; PMCID: PMC9909198.

  24. Hernandez CM, Høifødt H, Terry AV Jr (2003): Spontaneously hypertensive rats: further evaluation of age-related memory performance and cholinergic marker expression. J Psychiatry Neurosci. 2003 May;28(3):197-209. PMID: 12790160; PMCID: PMC161744.

  25. Ueno K, Togashi H, Matsumoto M, Ohashi S, Saito H, Yoshioka M (2002): Alpha4beta2 nicotinic acetylcholine receptor activation ameliorates impairment of spontaneous alternation behavior in stroke-prone spontaneously hypertensive rats, an animal model of attention deficit hyperactivity disorder. J Pharmacol Exp Ther. 2002 Jul;302(1):95-100. doi: 10.1124/jpet.302.1.95. PMID: 12065705.

  26. De Bruin NM, Kiliaan AJ, De Wilde MC, Broersen LM (2003): Combined uridine and choline administration improves cognitive deficits in spontaneously hypertensive rats. Neurobiol Learn Mem. 2003 Jul;80(1):63-79. doi: 10.1016/s1074-7427(03)00024-8. PMID: 12737935.

  27. Anderson LG, Vogiatzoglou E, Tang S, Luiz S, Duque T, Ghaly JP, Schwartzer JJ, Hales JB, Sabariego M (2023): Memory deficits and hippocampal cytokine expression in a rat model of ADHD. Brain Behav Immun Health. 2023 Nov 18;35:100700. doi: 10.1016/j.bbih.2023.100700. PMID: 38107021; PMCID: PMC10724493.

  28. Natsheh, Shiflett (2015): The Effects of Methylphenidate on Goal-directed Behavior in a Rat Model of ADHD. Front Behav Neurosci. 2015 Nov 25;9:326. doi: 10.3389/fnbeh.2015.00326. PMID: 26635568; PMCID: PMC4659329.

  29. Carboni E, Silvagni A, Valentini V, Di Chiara G (2003): Effect of amphetamine, cocaine and depolarization by high potassium on extracellular dopamine in the nucleus accumbens shell of SHR rats. An in vivo microdyalisis study. Neurosci Biobehav Rev. 2003 Nov;27(7):653-9. doi: 10.1016/j.neubiorev.2003.08.008. PMID: 14624809.

  30. Iams, McMurtry, Wexler (1979): Aldosterone, Deoxycorticosterone, Corticosterone, and Prolactin Changes during the Lifespan of Chronically and Spontaneously Hypertensive Rats; Endocrinology, Volume 104, Issue 5, 1 May 1979, Pages 1357–1363,

  31. Wolf, Calabrese (2020): Stressmedizin & Stresspsychologie, S. 55

  32. Olszyński, Polowy, Wardak, Grymanowska, Zieliński, Filipkowski (202): Spontaneously hypertensive rats manifest deficits in emotional response to 22-kHz and 50-kHz ultrasonic playback. Prog Neuropsychopharmacol Biol Psychiatry. 2022 Aug 22:110615. doi: 10.1016/j.pnpbp.2022.110615. PMID: 36007820.

  33. Adriani, Caprioli, Granstrem, Carli, Laviola (2003): The spontaneously hypertensive-rat as an animal model of ADHD: evidence for impulsive and non-impulsive subpopulations. Neurosci Biobehav Rev. 2003 Nov;27(7):639-51. doi: 10.1016/j.neubiorev.2003.08.007. PMID: 14624808.

  34. Woodman (1979): Biochemistry of psychopathy. J Psychosom Res. 1979;23(6):343-60. doi: 10.1016/0022-3999(79)90046-1. PMID: 549972, zitiert nach Henry (1997): Psychological and physiological responses to stress: the right hemisphere and the hypothalamo-pituitary-adrenal axis, an inquiry into problems of human bonding. Acta Physiol Scand Suppl. 1997;640:10-25. PMID: 9401599. REVIEW

  35. Leffa, Panzenhagen, Salvi, Bau, Pires, Torres, Rohde, Rovaris, Grevet (2019); Systematic review and meta-analysis of the behavioral effects of methylphenidate in the spontaneously hypertensive rat model of attention-deficit/hyperactivity disorder. Neurosci Biobehav Rev. 2019 Feb 28;100:166-179. doi: 10.1016/j.neubiorev.2019.02.019. METASTUDIE

  36. Roessner, Sagvolden, Das Banerjee, Middleton, Faraone, Walaas, Becker, Rothenberger, Bock (2010): Methylphenidate normalizes elevated dopamine transporter densities in an animal model of the attention-deficit/hyperactivity disorder combined type, but not to the same extent in one of the attention-deficit/hyperactivity disorder inattentive type. Neuroscience. 2010 Jun 2;167(4):1183-91. doi: 10.1016/j.neuroscience.2010.02.073. PMID: 20211696.

  37. Roessner, Manzke, Becker, Rothenberger, Bock (2009): Development of 5-HT transporter density and long-term effects of methylphenidate in an animal model of ADHD. World J Biol Psychiatry. 2009;10(4 Pt 2):581-5. doi: 10.1080/15622970802653709. PMID: 19172439.

  38. Wu, Zhao, Zhu, Peng, Jia, Wu, Zheng, Wu (2010): A novel function of microRNA let-7d in regulation of galectin-3 expression in attention deficit hyperactivity disorder rat brain. Brain Pathol. 2010 Nov;20(6):1042-54. doi: 10.1111/j.1750-3639.2010.00410.x.

  39. Isık, Kılıç, Demirdas, Aktepe, Aydogan Avsar (2020): Serum Galectin-3 Levels in Children with Attention-Deficit/Hyperactivity Disorder. Psychiatry Investig. 2020 Mar;17(3):256-261. doi: 10.30773/pi.2019.0247. PMID: 32151128; PMCID: PMC7113172. n = 70

  40. Leo, Sorrentino, Volpicelli, Eyman, Greco, Viggiano, di Porzio, Perrone-Capano (2003): Altered midbrain dopaminergic neurotransmission during development in an animal model of ADHD. Neurosci Biobehav Rev. 2003 Nov;27(7):661-9. doi: 10.1016/j.neubiorev.2003.08.009. PMID: 14624810. REVIEW

  41. Tsuda, Tsuda, Goldstein, Nishio, Masuyama (1996): Glutamatergic regulation of [3H]acetylcholine release in striatal slices of normotensive and spontaneously hypertensive rats. Neurochem Int. 1996 Sep;29(3):231-7. doi: 10.1016/0197-0186(96)00001-0. PMID: 8885281.

  42. Mill J, Sagvolden T, Asherson P (2005): Sequence analysis of Drd2, Drd4, and Dat1 in SHR and WKY rat strains. Behav Brain Funct. 2005 Dec 15;1:24. doi: 10.1186/1744-9081-1-24. PMID: 16356184; PMCID: PMC1363350.

  43. Watanabe Y, Fujita M, Ito Y, Okada T, Kusuoka H, Nishimura T (1997): Brain dopamine transporter in spontaneously hypertensive rats. J Nucl Med. 1997 Mar;38(3):470-4. PMID: 9074541.

  44. Kirouac GJ, Ganguly PK (1993): Up-regulation of dopamine receptors in the brain of the spontaneously hypertensive rat: an autoradiographic analysis. Neuroscience. 1993 Jan;52(1):135-41. doi: 10.1016/0306-4522(93)90188-l. PMID: 8433803.

  45. Linthorst AC, De Lang H, De Jong W, Versteeg DH (1991): Effect of the dopamine D2 receptor agonist quinpirole on the in vivo release of dopamine in the caudate nucleus of hypertensive rats. Eur J Pharmacol. 1991 Aug 29;201(2-3):125-33. doi: 10.1016/0014-2999(91)90335-n. PMID: 1686754.

  46. van den Buuse M, Linthorst AC, Versteeg DH, de Jong W (1991): Role of brain dopamine systems in the development of hypertension in the spontaneously hypertensive rat. Clin Exp Hypertens A. 1991;13(5):653-9. doi: 10.3109/10641969109042068. PMID: 1685356.

  47. Russell VA (2000): The nucleus accumbens motor-limbic interface of the spontaneously hypertensive rat as studied in vitro by the superfusion slice technique. Neurosci Biobehav Rev. 2000 Jan;24(1):133-6. doi: 10.1016/s0149-7634(99)00056-1. PMID: 10654669. REVIEW

  48. Fujita, Okutsu, Yamaguchi, Nakamura, Adachi, Saigusa, Koshikawa (2003): Altered pre- and postsynaptic dopamine receptor functions in spontaneously hypertensive rat: an animal model of attention-deficit hyperactivity disorder. J Oral Sci. 2003 Jun;45(2):75-83. doi: 10.2334/josnusd.45.75. PMID: 12930130.

  49. Li, Lu, Antonio, Mak, Rudd, Fan, Yew (2007): The usefulness of the spontaneously hypertensive rat to model attention-deficit/hyperactivity disorder (ADHD) may be explained by the differential expression of dopamine-related genes in the brain. Neurochem Int. 2007 May;50(6):848-57. doi: 10.1016/j.neuint.2007.02.005. PMID: 17395336.

  50. Fujita S, Okutsu H, Yamaguchi H, Nakamura S, Adachi K, Saigusa T, Koshikawa N (2003): Altered pre- and postsynaptic dopamine receptor functions in spontaneously hypertensive rat: an animal model of attention-deficit hyperactivity disorder. J Oral Sci. 2003 Jun;45(2):75-83. doi: 10.2334/josnusd.45.75. PMID: 12930130.

  51. Kirouac GJ, Ganguly PK (1995): Cholecystokinin-induced release of dopamine in the nucleus accumbens of the spontaneously hypertensive rat. Brain Res. 1995 Aug 21;689(2):245-53. doi: 10.1016/0006-8993(95)00584-d. PMID: 7583328.

  52. Ferguson SA, Gough BJ, Cada AM (2003): In vivo basal and amphetamine-induced striatal dopamine and metabolite levels are similar in the spontaneously hypertensive, Wistar-Kyoto and Sprague-Dawley male rats. Physiol Behav. 2003 Oct;80(1):109-14. doi: 10.1016/s0031-9384(03)00214-2. PMID: 14568315.

  53. Russell (2002): Hypodopaminergic and hypernoradrenergic activity in prefrontal cortex slices of an animal model for attention-deficit hyperactivity disorder–the spontaneously hypertensive rat. Behav Brain Res. 2002 Mar 10;130(1-2):191-6. doi: 10.1016/s0166-4328(01)00425-9. PMID: 11864734.

  54. Miller, Pomerleau, Huettl, Russell, Gerhardt, Glaser (2012): The spontaneously hypertensive and Wistar Kyoto rat models of ADHD exhibit sub-regional differences in dopamine release and uptake in the striatum and nucleus accumbens. Neuropharmacology. 2012 Dec;63(8):1327-34. doi: 10.1016/j.neuropharm.2012.08.020. PMID: 22960443; PMCID: PMC3485688.

  55. Heal DJ, Smith SL, Kulkarni RS, Rowley HL (2008): New perspectives from microdialysis studies in freely-moving, spontaneously hypertensive rats on the pharmacology of drugs for the treatment of ADHD. Pharmacol Biochem Behav. 2008 Aug;90(2):184-97. doi: 10.1016/j.pbb.2008.03.016. PMID: 18456311.

  56. Gungor Aydin A, Adiguzel E (2023): The mesocortical dopaminergic system cannot explain hyperactivity in an animal model of attention deficit hyperactivity disorder (ADHD)- Spontaneously hypertensive rats (SHR). Lab Anim Res. 2023 Sep 14;39(1):20. doi: 10.1186/s42826-023-00172-5. PMID: 37710339; PMCID: PMC10500870.

  57. Yamada, Goto, Ishii, Yoshioka, Matsuoka, Sugimoto (1992): Plasma adenosine concentrations are elevated in conscious spontaneously hypertensive rats. Clin Exp Pharmacol Physiol. 1992 Aug;19(8):563-7. doi: 10.1111/j.1440-1681.1992.tb00505.x. PMID: 1526061.

  58. Pandolfo, Machado, Köfalvi, Takahashi, Cunha (2013): Caffeine regulates frontocorticostriatal dopamine transporter density and improves attention and cognitive deficits in an animal model of attention deficit hyperactivity disorder. Eur Neuropsychopharmacol. 2013 Apr;23(4):317-28. doi: 10.1016/j.euroneuro.2012.04.011. PMID: 22561003.

  59. Sousa-Oliveira, Brandão, Vojtek, Gonçalves-Monteiro, Sousa, Diniz (2019): Vascular impairment of adenosinergic system in hypertension: increased adenosine bioavailability and differential distribution of adenosine receptors and nucleoside transporters. Histochem Cell Biol. 2019 May;151(5):407-418. doi: 10.1007/s00418-018-1743-0. PMID: 30357508.

  60. Pires, Pamplona, Pandolfo, Fernandes, Prediger, Takahashi (2009): Adenosine receptor antagonists improve short-term object-recognition ability of spontaneously hypertensive rats: a rodent model of attention-deficit hyperactivity disorder. Behav Pharmacol. 2009 Mar;20(2):134-45. doi: 10.1097/FBP.0b013e32832a80bf. PMID: 19307960.

  61. Prediger, Fernandes, Takahashi (2005): Blockade of adenosine A2A receptors reverses short-term social memory impairments in spontaneously hypertensive rats. Behav Brain Res. 2005 Apr 30;159(2):197-205. doi: 10.1016/j.bbr.2004.10.017. PMID: 15817183.

  62. Prediger, Pamplona, Fernandes, Takahashi (2005): Caffeine improves spatial learning deficits in an animal model of attention deficit hyperactivity disorder (ADHD) – the spontaneously hypertensive rat (SHR). Int J Neuropsychopharmacol. 2005 Dec;8(4):583-94. doi: 10.1017/S1461145705005341. PMID: 15877934.

  63. Pires, Pamplona, Pandolfo, Prediger, Takahashi (2010): Chronic caffeine treatment during prepubertal period confers long-term cognitive benefits in adult spontaneously hypertensive rats (SHR), an animal model of attention deficit hyperactivity disorder (ADHD). Behav Brain Res. 2010 Dec 20;215(1):39-44. doi: 10.1016/j.bbr.2010.06.022. PMID: 20600342.

  64. Leffa, Ferreira, Machado, Souza, Rosa, de Carvalho, Kincheski, Takahashi, Porciúncula, Souza, Cunha, Pandolfo (2019): Caffeine and cannabinoid receptors modulate impulsive behavior in an animal model of attentional deficit and hyperactivity disorder. Eur J Neurosci. 2019 Jun;49(12):1673-1683. doi: 10.1111/ejn.14348. PMID: 30667546.

  65. Kubo, Su (1983): Effects of adenosine on [3H]norepinephrine release from perfused mesenteric arteries of SHR and renal hypertensive rats. Eur J Pharmacol. 1983 Feb 18;87(2-3):349-52. doi: 10.1016/0014-2999(83)90352-7. PMID: 6840196.

  66. Carrettiero, Almeida, Fior-Chadi (2008): Adenosine modulates alpha2-adrenergic receptors within specific subnuclei of the nucleus tractus solitarius in normotensive and spontaneously hypertensive rats. Hypertens Res. 2008 Dec;31(12):2177-86. doi: 10.1291/hypres.31.2177. PMID: 19139607.

  67. Sousa, Vieira-Rocha, Sá, Ferreirinha, Correia-de-Sá, Fresco, Diniz (2014): Lack of endogenous adenosine tonus on sympathetic neurotransmission in spontaneously hypertensive rat mesenteric artery. PLoS One. 2014 Aug 26;9(8):e105540. doi: 10.1371/journal.pone.0105540. PMID: 25158061; PMCID: PMC4144848.

  68. 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.

  69. Russell, Wiggins (2000): Increased glutamate-stimulated norepinephrine release from prefrontal cortex slices of spontaneously hypertensive rats. Metab Brain Dis. 2000 Dec;15(4):297-304. doi: 10.1023/a:1011175225512. PMID: 11383554.

  70. Kubo, Su (1983): Effects of adenosine on [3H] norepinephrine release from perfused mesenteric arteries of SHR and renal hypertensive rats. Eur J Pharmacol. 1983 Feb 18;87(2-3):349-52. doi: 10.1016/0014-2999(83)90352-7. PMID: 6840196.

  71. Russell, Sagvolden, Johansen (2005): Animal models of attention-deficit hyperactivity disorder. Behav Brain Funct. 2005 Jul 15;1:9. doi: 10.1186/1744-9081-1-9. PMID: 16022733; PMCID: PMC1180819.

  72. Kubrusly, da Rosa Valli, Ferreira, de Moura, Borges-Martins, Martins, Ferreira, Sathler, de Melo Reis, Ferreira, Manhães, Dos Santos Pereira (2021): Caffeine Improves GABA Transport in the Striatum of Spontaneously Hypertensive Rats (SHR). Neurotox Res. 2021 Dec;39(6):1946-1958. doi: 10.1007/s12640-021-00423-0.PMID: 34637050.

  73. Sterley, Howells, Russell (2013): Evidence for reduced tonic levels of GABA in the hippocampus of an animal model of ADHD, the spontaneously hypertensive rat. Brain Res. 2013 Dec 6;1541:52-60. doi: 10.1016/j.brainres.2013.10.023. PMID: 24161405.

  74. Yoon SY, dela Peña I, Kim SM, Woo TS, Shin CY, Son KH, Park H, Lee YS, Ryu JH, Jin M, Kim KM, Cheong JH (2013):Oroxylin A improves attention deficit hyperactivity disorder-like behaviors in the spontaneously hypertensive rat and inhibits reuptake of dopamine in vitro. Arch Pharm Res. 2013 Jan;36(1):134-40. doi: 10.1007/s12272-013-0009-6. PMID: 23371806.

  75. Kurtz, Portale, Morris Jr. (1986): Evidence for a difference in vitamin D metabolism between spontaneously hypertensive and Wistar-Kyoto rats. Hypertension. 1986 Nov;8(11):1015-20. doi: 10.1161/01.hyp.8.11.1015. PMID: 3770864.

  76. Schedl, Wilson, Horst (1988): Calcium transport and vitamin D in three breeds of spontaneously hypertensive rats. Hypertension. 1988 Sep;12(3):310-6. doi: 10.1161/01.hyp.12.3.310. PMID: 2844665.

  77. Hashimoto, Makino, Hirasawa, Takao, Sugaware, Murakami, Ono, Ota (1989): Abnormalities in the Hypothalamo-Pituitary-Adrenal Axis in Spontaneously Hypertensive Rats during Development of Hypertension; Endocrinology, Volume 125, Issue 3, 1 September 1989, Pages 1161–1167,

  78. Yamori, Ooshima, Okamoto (1973): Metabolism of Adrenal Corticosteroids in Spontaneously Hypertensive Rats; Japanese Heart Journal / 14 (1973) 2;

  79. Chen, Zheng, Xie, Huang, Ke, Zheng, Lu, Hu (2017): Glucocorticoids/glucocorticoid receptors effect on dopaminergic neurotransmitters in ADHD rats. Brain Res Bull. 2017 May;131:214-220. doi: 10.1016/j.brainresbull.2017.04.013.

  80. Lu, Zhang, Hong, Wang, Huang, Zheng, Chen (2018): [Effect of glucocorticoid receptor function on the behavior of rats with attention deficit hyperactivity disorder] [Article in Chinese]; Zhongguo Dang Dai Er Ke Za Zhi. 2018 Oct;20(10):848-853.

  81. Lin X, Huang L, Huang H, Ke Z, Chen Y (2023): Disturbed relationship between glucocorticoid receptor and 5-HT1AR/5-HT2AR in ADHD rats: A correlation study. Front Neurosci. 2023 Jan 9;16:1064369. doi: 10.3389/fnins.2022.1064369. PMID: 36699537; PMCID: PMC9869156.

  82. Brocca, Pietranera, de Kloet, De Nicola (2018): Mineralocorticoid Receptors, Neuroinflammation and Hypertensive Encephalopathy. Cell Mol Neurobiol. 2018 Aug 16. doi: 10.1007/s10571-018-0610-9.

  83. Wu, Peng, Yu, Zhao, Li, Jin, Jiang, Chen, Deng, Sun, Wu (2015): Circulating MicroRNA Let-7d in Attention-Deficit/Hyperactivity Disorder. Neuromolecular Med. 2015 Jun;17(2):137-46. doi: 10.1007/s12017-015-8345-y. n = 70

  84. Masubuchi, Kumai, Uematsu, Komoriyama (1982): Hirai Gonadectomy-induced reduction of blood pressure in adult spontaneously hypertensive rats. Acta Endocrinol September 1, 1982 101 154-160, doi: 10.1530/acta.0.1010154

  85. Watlington, Kramer, Schuetz, Zilai, Grogan, Guzelian, Gizek, Schoolwerth (1992): Corticosterone 6 beta-hydroxylation correlates with blood pressure in spontaneously hypertensive rats; 1 JUN 1992.

  86. Ghosha, McLean Grogan, Basua, Watlington (1993): Renal corticosterone 6β-hydroxylase in the spontaneously hypertensive rat; Biochimica et Biophysica Acta (BBA) – Molecular Basis of Disease, Volume 1182, Issue 2, 8 September 1993, Pages 152-156;

  87. McMurtry, Wexler (1981): Hypersensitivity of Spontaneously Hypertensive Rats (SHR) to Heat, Ether, and Immobilization, Endocrinology, Volume 108, Issue 5, 1 May 1981, Pages 1730–1736,

  88. Kozłowska, Wojtacha, Równiak, Kolenkiewicz, Huang (2019): ADHD pathogenesis in the immune, endocrine and nervous systems of juvenile and maturating SHR and WKY rats. Psychopharmacology (Berl). 2019 Feb 8. doi: 10.1007/s00213-019-5180-0.

  89. Leffa, Bellaver, de Oliveira, de Macedo, de Freitas, Grevet, Caumo, Rohde, Quincozes-Santos, Torres (2017): Increased Oxidative Parameters and Decreased Cytokine Levels in an Animal Model of Attention-Deficit/Hyperactivity Disorder. Neurochem Res. 2017 Nov;42(11):3084-3092. doi: 10.1007/s11064-017-2341-6.

  90. Chen, Hsu, Chen, Chou, Weng, Tzang (2017):Effects of taurine on resting-state fMRI activity in spontaneously hypertensive rats. PLoS One. 2017 Jul 10;12(7):e0181122. doi: 10.1371/journal.pone.0181122. eCollection 2017.

  91. Chen, Chiu, Chen, Hsu, Tzang (2018): Effects of taurine on striatal dopamine transporter expression and dopamine uptake in SHR rats; Behav Brain Res. 2018 Apr 22. pii: S0166-4328(18)30306-1. doi: 10.1016/j.bbr.2018.04.031.

  92. Chen VC, Hsu TC, Chen LJ, Chou HC, Weng JC, Tzang BS (2017): Effects of taurine on resting-state fMRI activity in spontaneously hypertensive rats. PLoS One. 2017 Jul 10;12(7):e0181122. doi: 10.1371/journal.pone.0181122. Erratum in: PLoS One. 2017 Dec 19;12 (12 ):e0190203. PMID: 28700674; PMCID: PMC5507323.

  93. Chen, Yuan, Sun, Song, Lu, Ni, Han (2019): Metabolomics study of the prefrontal cortex in a rat model of attention deficit hyperactivity disorder reveals the association between cholesterol metabolism disorder and hyperactive behavior. Biochem Biophys Res Commun. 2019 Dec 18. pii: S0006-291X(19)32336-8. doi: 10.1016/j.bbrc.2019.12.016.

  94. Xu, Yu, Zhao, Du, Xia, Su, Du, Yang, Qi, Li, Zhou, Zhu, Li, Kang (2020): Calcitriol ameliorated autonomic dysfunction and hypertension by down-regulating inflammation and oxidative stress in the paraventricular nucleus of SHR. Toxicol Appl Pharmacol. 2020 Mar 5:114950. doi: 10.1016/j.taap.2020.114950. PMID: 32147540.

  95. Bendel P, Eilam R (1992): Quantitation of ventricular size in normal and spontaneously hypertensive rats by magnetic resonance imaging. Brain Res. 1992 Mar 6;574(1-2):224-8. doi: 10.1016/0006-8993(92)90820-y. PMID: 1638395.

  96. Sabbatini M, Strocchi P, Vitaioli L, Amenta F (2000): The hippocampus in spontaneously hypertensive rats: a quantitative microanatomical study. Neuroscience. 2000;100(2):251-8. doi: 10.1016/s0306-4522(00)00297-9. PMID: 11008165.

  97. Droguerre, Vidal, Valdebenito, Mouthon, Zimmer, Charvériat (2022): Impaired Local and Long-Range Brain Connectivity and Visual Response in a Genetic Rat Model of Hyperactivity Revealed by Functional Ultrasound. Front Neurosci. 2022 Mar 24;16:865140. doi: 10.3389/fnins.2022.865140. PMID: 35401075; PMCID: PMC8987929.

  98. Alves, Almeida, Marques, Faé, Machado, Oliveira, Portela, Porciúncula (2020): Caffeine and adenosine A2A receptors rescue neuronal development in vitro of frontal cortical neurons in a rat model of attention deficit and hyperactivity disorder. Neuropharmacology. 2020 Apr;166:107782. doi: 10.1016/j.neuropharm.2019.107782. PMID: 31756336.

  99. Nishigaki, Yokoyama, Shimizu, Marumoto, Misumi, Ueda, Ishida, Shibuya, Hida (2018): Monosodium glutamate ingestion during the development period reduces aggression mediated by the vagus nerve in a rat model of attention deficit-hyperactivity disorder. Brain Res. 2018 Jul 1;1690:40-50. doi: 10.1016/j.brainres.2018.04.006. PMID: 29649467.

  100. Liu Y, Yang C, Meng Y, Dang Y, Yang L (2023): Ketogenic diet ameliorates attention deficit hyperactivity disorder in rats via regulating gut microbiota. PLoS One. 2023 Aug 16;18(8):e0289133. doi: 10.1371/journal.pone.0289133. PMID: 37585373.

  101. De Barros Oliveira R, Anselmi M, Marchette RCN, Roversi K, Fadanni GP, De Carvalho LM, Damasceno S, Heinrich IA, Leal RB, Cavalli J, Moreira-Júnior RE, Godard ALB, Izídio GS (2024): Differential expression of alpha-synuclein in the hippocampus of SHR and SLA16 isogenic rat strains. Behav Brain Res. 2024 Mar 12;461:114835. doi: 10.1016/j.bbr.2023.114835. PMID: 38151185.

  102. Shindo, Shikanai, Watarai, Hiraide, Iizuka, Izumi (2022): D-serine metabolism in the medial prefrontal cortex, but not the hippocampus, is involved in AD/HD-like behaviors in SHRSP/Ezo. Eur J Pharmacol. 2022 Mar 29;923:174930. doi: 10.1016/j.ejphar.2022.174930. PMID: 35364072.

  103. Suzuki N, Hiraide S, Shikanai H, Isshiki T, Yamaguchi T, Izumi T, Iizuka K (2024): Impaired monoamine neural system in the mPFC of SHRSP/Ezo as an animal model of attention-deficit/hyperactivity disorder. J Pharmacol Sci. 2024 Feb;154(2):61-71. doi: 10.1016/j.jphs.2023.12.002. PMID: 38246729.

  104. Custodio, Botanas, de la Peña, Dela Peña, Kim, Sayson, Abiero, Ryoo, Kim, Kim, Cheong (2018): Overexpression of the Thyroid Hormone-Responsive (THRSP) Gene in the Striatum Leads to the Development of Inattentive-like Phenotype in Mice. Neuroscience. 2018 Oct 15;390:141-150. doi: 10.1016/j.neuroscience.2018.08.008.

  105. Dela Peña, Shen, Shi (2021): Droxidopa alters dopamine neuron and prefrontal cortex activity and improves attention-deficit/hyperactivity disorder-like behaviors in rats. Eur J Pharmacol. 2021 Feb 5;892:173826. doi: 10.1016/j.ejphar.2020.173826. PMID: 33347825.

  106. Hess EJ, Jinnah HA, Kozak CA, Wilson MC (1992): Spontaneous locomotor hyperactivity in a mouse mutant with a deletion including the Snap gene on chromosome 2. J Neurosci. 1992 Jul;12(7):2865-74. doi: 10.1523/JNEUROSCI.12-07-02865.1992. PMID: 1613559; PMCID: PMC6575838.

  107. Hess EJ, Collins KA, Wilson MC (1996): Mouse model of hyperkinesis implicates SNAP-25 in behavioral regulation. J Neurosci. 1996 May 1;16(9):3104-11. doi: 10.1523/JNEUROSCI.16-09-03104.1996. PMID: 8622140; PMCID: PMC6579059.

  108. Heyser CJ, Wilson MC, Gold LH (1995): Coloboma hyperactive mutant exhibits delayed neurobehavioral developmental milestones. Brain Res Dev Brain Res. 1995 Nov 21;89(2):264-9. doi: 10.1016/0165-3806(95)00130-6. PMID: 8612329.

  109. Wilson MC (2000): Coloboma mouse mutant as an animal model of hyperkinesis and attention deficit hyperactivity disorder. Neurosci Biobehav Rev. 2000 Jan;24(1):51-7. doi: 10.1016/s0149-7634(99)00064-0. PMID: 10654661.

  110. Jones, Hess (2003): Norepinephrine regulates locomotor hyperactivity in the mouse mutant coloboma. Pharmacol Biochem Behav. 2003 Apr;75(1):209-16. doi: 10.1016/s0091-3057(03)00073-x. PMID: 12759129.

  111. Bouchatta, Manouze, Ba-M’Hamed, Landry, Bennis (2020): Neonatal 6-OHDA Lesion Model in Mouse Induces Cognitive Dysfunctions of Attention-Deficit/Hyperactivity Disorder (ADHD) During Young Age. Front Behav Neurosci. 2020 Feb 26;14:27. doi: 10.3389/fnbeh.2020.00027. PMID: 32174817; PMCID: PMC7054716.

  112. Bruno KJ, Freet CS, Twining RC, Egami K, Grigson PS, Hess EJ (2007): Abnormal latent inhibition and impulsivity in coloboma mice, a model of ADHD. Neurobiol Dis. 2007 Jan;25(1):206-16. doi: 10.1016/j.nbd.2006.09.009. PMID: 17064920; PMCID: PMC1761697.

  113. Raber, Mehta, Kreifeldt, Parsons, Weiss, Bloom, Wilson (1997): Coloboma hyperactive mutant mice exhibit regional and transmitter-specific deficits in neurotransmission. J Neurochem. 1997 Jan;68(1):176-86. doi: 10.1046/j.1471-4159.1997.68010176.x. PMID: 8978724.

  114. Bruno KJ, Hess EJ (2006) The alpha(2C)-adrenergic receptor mediates hyperactivity of coloboma mice, a model of attention deficit hyperactivity disorder. Neurobiol Dis. 2006 Sep;23(3):679-88. doi: 10.1016/j.nbd.2006.05.007. PMID: 16839770.

  115. Jones, Williams, Hess (2001): Expression of catecholaminergic mRNAs in the hyperactive mouse mutant coloboma. Brain Res Mol Brain Res. 2001 Nov 30;96(1-2):114-21. doi: 10.1016/s0169-328x(01)00281-9. PMID: 11731016.

  116. Jones, Williams, Hess (2001): Abnormal presynaptic catecholamine regulation in a hyperactive SNAP-25-deficient mouse mutant. Pharmacol Biochem Behav. 2001 Apr;68(4):669-76. doi: 10.1016/s0091-3057(01)00481-6. PMID: 11526963.

  117. Bouchatta, Manouze, Bouali-Benazzouz, Kerekes, Ba-M’hamed, Fossat, Landry, Bennis (2018): Neonatal 6-OHDA lesion model in mouse induces Attention-Deficit/ Hyperactivity Disorder (ADHD)-like behaviour. Sci Rep. 2018 Oct 18;8(1):15349. doi: 10.1038/s41598-018-33778-0.

  118. Luthman, Fredriksson, Lewander, Jonsson, Archer (1989): Effects of d-amphetamine and methylphenidate on hyperactivity produced by neonatal 6-hydroxydopamine treatment. Psychopharmacology (Berl). 1989;99(4):550-7. doi: 10.1007/BF00589907. PMID: 2594922.

  119. Avale ME, Falzone TL, Gelman DM, Low MJ, Grandy DK, Rubinstein M (2004): The dopamine D4 receptor is essential for hyperactivity and impaired behavioral inhibition in a mouse model of attention deficit/hyperactivity disorder. Mol Psychiatry. 2004 Jul;9(7):718-26. doi: 10.1038/ PMID: 14699433.

  120. Shaywitz BA, Klopper JH, Gordon JW (1978): Methylphenidate in 6-hydroxydopamine-treated developing rat pups. Effects on activity and maze performance. Arch Neurol. 1978 Jul;35(7):463-9. doi: 10.1001/archneur.1978.00500310065014. PMID: 566540.

  121. Davids E, Zhang K, Kula NS, Tarazi FI, Baldessarini RJ (2002): Effects of norepinephrine and serotonin transporter inhibitors on hyperactivity induced by neonatal 6-hydroxydopamine lesioning in rats. J Pharmacol Exp Ther. 2002 Jun;301(3):1097-102. doi: 10.1124/jpet.301.3.1097. PMID: 12023542.

  122. Sifeddine W, Ba-M’hamed S, Landry M, Bennis M (2023): Effect of atomoxetine on ADHD-pain hypersensitization comorbidity in 6-OHDA lesioned mice. Pharmacol Rep. 2023 Feb 14. doi: 10.1007/s43440-023-00459-3. PMID: 36787018.

  123. Zhang, Tarazi, Baldessarini (2001): Role of dopamine D(4) receptors in motor hyperactivity induced by neonatal 6-hydroxydopamine lesions in rats. Neuropsychopharmacology. 2001 Nov;25(5):624-32. doi: 10.1016/S0893-133X(01)00262-7. PMID: 11682245.

  124. Zhang K, Davids E, Tarazi FI, Baldessarini RJ (2002): Effects of dopamine D4 receptor-selective antagonists on motor hyperactivity in rats with neonatal 6-hydroxydopamine lesions. Psychopharmacology (Berl). 2002 Apr;161(1):100-6. doi: 10.1007/s00213-002-1018-1. PMID: 11967637.

  125. Zhang, Davids, Tarazi, Baldessarini (2002): Serotonin transporter binding increases in caudate-putamen and nucleus accumbens after neonatal 6-hydroxydopamine lesions in rats: implications for motor hyperactivity. Brain Res Dev Brain Res. 2002 Aug 30;137(2):135-8. doi: 10.1016/s0165-3806(02)00436-4. PMID: 12220705.

  126. Morello, Voikar, Parkkinen, Panhelainen, Rosenholm, Makkonen, Rantamäki, Piepponen, Aitta-Aho, Partanen (2020): ADHD-like behaviors caused by inactivation of a transcription factor controlling the balance of inhibitory and excitatory neuron development in the mouse anterior brainstem. Transl Psychiatry. 2020 Oct 21;10(1):357. doi: 10.1038/s41398-020-01033-8. PMID: 33087695; PMCID: PMC7578792.

  127. Custodio RJP, Kim M, Chung YC, Kim BN, Kim HJ, Cheong JH (2023): Thrsp Gene and the ADHD Predominantly Inattentive Presentation. ACS Chem Neurosci. 2023 Feb 15;14(4):573-589. doi: 10.1021/acschemneuro.2c00710. Epub 2023 Jan 30. PMID: 36716294. REVIEW

  128. Custodio RJP, Kim HJ, Kim J, Ortiz DM, Kim M, Buctot D, Sayson LV, Lee HJ, Kim BN, Yi EC, Cheong JH (2023): Hippocampal dentate gyri proteomics reveals Wnt signaling involvement in the behavioral impairment in the THRSP-overexpressing ADHD mouse model. Commun Biol. 2023 Jan 16;6(1):55. doi: 10.1038/s42003-022-04387-5. PMID: 36646879; PMCID: PMC9842619.

  129. Bai WJ, Luo XG, Jin BH, Zhu KS, Guo WY, Zhu XQ, Qin X, Yang ZX, Zhao JJ, Chen SR, Wang R, Hao J, Wang F, Shi YS, Kong DZ, Zhang W. (2022): Deficiency of transmembrane AMPA receptor regulatory protein γ-8 leads to attention-deficit hyperactivity disorder-like behavior in mice. Zool Res. 2022 Sep 18;43(5):851-870. doi: 10.24272/j.issn.2095-8137.2022.122. PMID: 36031768.

  130. Anzalone A, Lizardi-Ortiz JE, Ramos M, De Mei C, Hopf FW, Iaccarino C, Halbout B, Jacobsen J, Kinoshita C, Welter M, Caron MG, Bonci A, Sulzer D, Borrelli E (2012): Dual control of dopamine synthesis and release by presynaptic and postsynaptic dopamine D2 receptors. J Neurosci. 2012 Jun 27;32(26):9023-34. doi: 10.1523/JNEUROSCI.0918-12.2012. PMID: 22745501; PMCID: PMC3752062.

  131. Bello EP, Mateo Y, Gelman DM, Noaín D, Shin JH, Low MJ, Alvarez VA, Lovinger DM, Rubinstein M (2011): Cocaine supersensitivity and enhanced motivation for reward in mice lacking dopamine D2 autoreceptors. Nat Neurosci. 2011 Jul 10;14(8):1033-8. doi: 10.1038/nn.2862. PMID: 21743470; PMCID: PMC3175737.

  132. Holroyd KB, Adrover MF, Fuino RL, Bock R, Kaplan AR, Gremel CM, Rubinstein M, Alvarez VA (2015): Loss of feedback inhibition via D2 autoreceptors enhances acquisition of cocaine taking and reactivity to drug-paired cues. Neuropsychopharmacology. 2015 May;40(6):1495-509. doi: 10.1038/npp.2014.336. PMID: 25547712; PMCID: PMC4397408.

  133. Dickinson SD, Sabeti J, Larson GA, Giardina K, Rubinstein M, Kelly MA, Grandy DK, Low MJ, Gerhardt GA, Zahniser NR (1999): Dopamine D2 receptor-deficient mice exhibit decreased dopamine transporter function but no changes in dopamine release in dorsal striatum. J Neurochem. 1999 Jan;72(1):148-56. doi: 10.1046/j.1471-4159.1999.0720148.x. PMID: 9886065.

  134. Benoit-Marand M, Borrelli E, Gonon F (2001): Inhibition of dopamine release via presynaptic D2 receptors: time course and functional characteristics in vivo. J Neurosci. 2001 Dec 1;21(23):9134-41. doi: 10.1523/JNEUROSCI.21-23-09134.2001. PMID: 11717346; PMCID: PMC6763925.

  135. Schmitz Y, Schmauss C, Sulzer D. Altered dopamine release and uptake kinetics in mice lacking D2 receptors. J Neurosci. 2002 Sep 15;22(18):8002-9. doi: 10.1523/JNEUROSCI.22-18-08002.2002. PMID: 12223553; PMCID: PMC6758092.

  136. Enard, Gehre, Hammerschmidt, Hölter, Blass, Somel, Brückner, Schreiweis, Winter, Sohr, Becker, Wiebe, Nickel, Giger, Müller, Groszer, Adler, Aguilar, Bolle, Calzada-Wack, Dalke, Ehrhardt, Favor, Fuchs, Gailus-Durner, Hans, Hölzlwimmer, Javaheri, Kalaydjiev, Kallnik, Kling, Kunder, Mossbrugger, Naton, Racz, Rathkolb, Rozman, Schrewe, Busch, Graw, Ivandic, Klingenspor, Klopstock, Ollert, Quintanilla-Martinez, Schulz, Wolf, Wurst, Zimmer, Fisher, Morgenstern, Arendt, de Angelis, Fischer, Schwarz, Pääbo (2009): A humanized version of Foxp2 affects cortico-basal ganglia circuits in mice. Cell. 2009 May 29;137(5):961-71. doi: 10.1016/j.cell.2009.03.041. PMID: 19490899.

  137. Xu F, Gainetdinov RR, Wetsel WC, Jones SR, Bohn LM, Miller GW, Wang YM, Caron MG (2000): Mice lacking the norepinephrine transporter are supersensitive to psychostimulants. Nat Neurosci. 2000 May;3(5):465-71. doi: 10.1038/74839. PMID: 10769386.

Diese Seite wurde am 16.04.2024 zuletzt aktualisiert.