ADHD animal models with unknown dopamine changes

In this post, we are compiling animal models of ADHD in which we have not yet determined the mechanism underlying the changes in dopamine levels.

3.1. 39,XY O–Mouse (DHEA deficiency) (dopamine unchanged)*¶

39,XY*O-mice are genetically unable to produce steroid sulfatase (STS). Among other things, STS breaks down the steroid DHEAS into DHEA.

Compared to 40,XY mice, 39,XY*O mice showed:¹

• increased reactivity to a new environment¹
• Hyperactivity during the active phase¹
• Inattention²
• increased emotional reactivity¹
• increased water consumption (but not food)¹
• increased motivation²
• no difference in social dominance¹
• significantly lower serum DHEA levels¹
• equivalent corticosterone levels¹
• Increases serotonin²
  • in the striatum
  • in the hippocampus
• Reduced serotonin turnover²
  • in the striatum
  • in the hippocampus
• Reduced norepinephrine turnover²
  • in the striatum
• MOPEG reduces levels in the striatum²
• Dopamine levels remain unchanged in the prefrontal cortex, striatum, hippocampus, thalamus, and cerebellum²

We find it interesting that dopamine levels in the brain remain unchanged, even though STS can convert dopamine sulfate into dopamine. This could be an indication that dopamine synthesis mediated by STS does not play a significant role in the brain.

The STS gene is a candidate gene for ADHD.

3.2. GIT1-KO mouse (reduced dopamine activity?)¶

The G-protein-coupled receptor kinase 1 knockout mouse (GIT1-KO) serves as an animal model for research on ADHD.³⁴
The GIT1-KO mouse exhibits the following ADHD symptoms:⁵

• Hyperactivity
  • treatable with amphetamine and methylphenidate
• Learning Disabilities
• Memory loss
• no impulsivity⁶
• no inattention⁶

GIT1 regulates dopamine receptors. Overexpression of GIT1 disrupts the internalization of numerous G-protein-coupled receptors, including dopamine receptors.⁷ The latter suggests a model of reduced dopamine signaling.
GIT1 is a candidate gene for ADHD.

Compared to wild-type mice, GIT1-KO mice showed⁴

• reduced glial GABA levels
• a reduction in the tonic current from the cerebellar granule cells

3.3. ATXN7 Overexpressed Mouse¶

The ATXN7-overexpressing mice (ATXN7-OE) exhibit

• Hyperactivity
• Impulsivity
• no inattention

This corresponds to the ADHD-HI subtype.
The Ataxin-7 gene (ATXN7) is associated with hyperactivity. ATXN7-OE mice exhibit overexpression of the Atxn7 gene and protein in the PFC and striatum. Atomoxetine (3 mg/kg, intraperitoneal) reduces ADHD-HI-like behavior and ATXN7 gene expression in the PFC and striatum.⁸

3.4. Grin1 mouse¶

Grin1 mice are a heterozygous mutant strain. Grin1 (glutamate [NMDA] receptor subunit zeta-1) encodes a protein that is essential for the function of NMDA receptors. Grin2B may be associated with ADHD. Grin1 mice exhibit:

• Hyperactivity⁹
• Novelty Seeking⁹
• Reduced social interaction⁹
• Anxiety¹⁰

The attentional abilities of Grin1 mice have not yet been studied.⁹

Hyperactivity improved with high-dose methylphenidate. While c-FOS levels in the prelimbic cortex and striatum were very low in control mice and increased with MPH, c-FOS levels in the prelimbic cortex were high in GRIN1Rgsc174⁄+ mice and were reduced by MPH (at a very high dose). GRIN1Rgsc174⁄+ mice also exhibited increased phosphorylation of the ERK2 protein in the nucleus accumbens, which remained barely unchanged even after an extremely high dose of MPH (30 mg/kg). The authors concluded that the behavioral symptoms of the GRIN1 mouse are underlain by NMDA receptor dysfunction in the relevant brain regions, and that the effect of MPH in the GRIN1 mouse is not specifically mediated via the DAT but rather via other receptors or mechanisms, since the DAT should have shown an effect even at significantly lower doses.¹⁰ The authors also point out the similarly altered glutamatergic neurotransmission in SHRs. SHRs do not respond at all to MPH with regard to hyperactivity, but do respond to AMP (see there).

3.5. AGCYAP1-KO mouse¶

The Adcyap1 gene encodes the neuropeptide adenylate cyclase-activating polypeptide 1, which is produced in the pituitary gland. Mice lacking the ADXAP1 gene (Adcyap1(-/-)), exhibit increased novelty seeking and hyperactivity. One study found sensorimotor gating deficits in these mice, manifested as deficits in prepulse inhibition (PPI). Amphetamine was able to normalize PPI and hyperactivity. This occurred via serotonin-1A (5-HT(1A)) receptor signaling.¹¹ Wild-type mice also developed hyperactivity in response to the 5-HT(1A) agonist 8-hydroxy-2-(di-n-propylamino)tetralin, which could likewise be reversed by AMP. In AGCYAP1-KO mice treated with AMP, increased levels of c-Fos-positive neurons were also observed in the PFC, suggesting enhanced inhibitory control by prefrontal neurons.¹²

3.6. Guanylyl cyclase C knockout mouse (GC-C-KO mouse)¶

Guanylyl cyclase-C (GC-C) is a membrane receptor found, along with tyrosine hydroxylase, in the VTA and the substantia nigra pars compacta. GC-C can modulate dopamine signaling. Activation of GC-C by GC-C ligands, such as guanylin or uroguanylin, potentiates the excitatory responses mediated by glutamate and acetylcholine receptors via the activity of guanosine-3’,5’-monophosphate-dependent protein kinase (PKG), which affects dopaminergic cells.

GC-C-KO mice show:

• Hyperactivity (?)
  • in familiar and new environments¹³
  • is repealed by
    • systemic AMP injection¹³
    • GMP-dependent protein kinase agonist infusion into the VTA¹³
  • Another study found no evidence of hyperactivity¹⁴
• Attention deficit in the Go/No-Go test.¹³
  • is repealed by
    • systemic AMP injection¹³
    • GMP-dependent protein kinase agonist infusion into the VTA¹³
• Extensive exploration of new smells¹³
• Detection of new objects is affected¹⁴
• Reduces tactile startle¹⁴
• Acoustic alarm remains unchanged¹⁴
• Increased latency during training trials in the Morris water maze observed only in females¹⁴
  • not in spatial learning experiments with a hidden platform

3.7. GAT1 knockout mouse¶

Tonic GABA inhibits dopamine release in the striatum (of the mouse) via GABA-A and GABA-B receptors. There are only a few GABAergic synapses on dopamine axons. Therefore, the tonic inhibition of dopamine release by striatal GABA is likely mediated by extrasynaptic effects of extracellular GABA on receptors that are presumably located on dopamine axons. GABA thus exerts extrasynaptic effects on other neurons.
Gamma-aminobutyric acid transporters of subtypes 1 and 3 reuptake GABA. If the GABA transporters GAT1 or GAT3 are reduced or inactivated, this increases extracellular GABA and thereby reduces dopamine release in the dorsal striatum, but not in the nucleus accumbens.¹⁵¹⁶

The two isoforms of GAT in the striatum are:

• GAT-1 (Slc6a1)
  • common in the axons of GABAergic neurons
  • in striatal astrocytes
  • in DA midbrain neurons
  • on striatal DA axons
• GAT-3 (Slc6a11)
  • moderately expressed
  • found primarily in (striatal) astrocytes
    • Dysregulation of GAT-3 on striatal astrocytes causes a profound alteration in SPN activity and striatal-controlled behavior through reduced extracellular dopamine¹⁷
  • s in DA midbrain neurons
  • on striatal DA axons

(GAT1)-KO mice (GAT-1-/- mice) exhibit typical ADHD symptoms:¹⁸¹⁹

• Hyperactivity
  • AMP and MPH reduce these
• motor problems
  • Ataxia, characterized by impaired motor coordination and balance
• Attention problems
  • Impaired ability to focus attention in an “incentive runway test”
• Impulsivity in a passive avoidance incentive test
• Memory problems
  • Deficits in spatial reference memory

3.8. TR-beta 1 transgenic mouse¶

Carries a mutated human thyroid receptor TRβ1 gene.

TRbeta-transgenic mice²⁰

• are euthyroid (i.e., have normal levels of the thyroid hormones triiodothyronine (T3) and thyroxine (T4)), except for a brief period during postnatal development.
• continue into adulthood
  • Changes in the dopaminergic system (increased dopamine turnover)
  • ADHD symptoms
  • paradoxical reaction to MPH

Like the vast majority of children with ADHD, TRβ1 transgenic mice thus exhibit ADHD symptoms without measurable thyroid abnormalities. It is possible that even temporary disorders in developmental thyroid homeostasis can lead to long-lasting behavioral and cognitive consequences, including the development of the full spectrum of ADHD symptoms.

Symptoms:

• Hyperactivity
• Impulsivity
• Inattention
• All symptoms
  • Are reduced by methylphenidate
  • Are dynamic, just as with ADHD, and are highly sensitive to changes in environmental conditions, stress, and reinforcement

3.9. FEZ1-KO mouse¶

The Fez1 gene (fasciculation and elongation protein zeta-1) is specifically expressed in the nervous system and plays a role in neurodevelopment.
FEZ1 knockout mice show:²¹

• Hyperactivity²²
• Impulsivity
• Reduced tyrosine hydroxylase expression in the midbrain and brainstem
• Reduced levels of dopamine and norepinephrine, as well as their metabolites, in the nucleus accumbens and PFC
• MPH and guanfacine caused
  • Improves hyperactivity and impulsivity
  • Dopamine and norepinephrine levels in the nucleus accumbens and PFC were restored
  • Increased tyrosine hydroxylase expression

The FEZ1 gene is specifically expressed in the nervous system, with expression peaking during neurodevelopment. FEZ1 is involved in various neurodevelopmental processes, such as:²¹

• Neurite outgrowth
• dendritic branching
• axonal transport
• neuronal migration

3.10. STA3GAL5(-/-) - Mouse¶

St3gal5-/- mice. In contrast to B4galnt1-/- mice, the clinical abnormalities in these mutants regress only partially, which could be due to compensatory synthesis of the 0-series gangliosides GD1α and GM1b. However, the
St3gal5-/- mice lack the major CNS gangliosides GM3, GM1, GD1a, GD3, GT1b, and GQ1b
St3gal5-/- mice show:²³

• motor hyperactivity
• Impulsivity
• Inattention²⁴
• increased insulin sensitivity²⁵
• autistic behaviors²⁶
  • Impaired conditioned taste aversion in an inhibitory learning task
  • anxiety-like behavior in the wild
  • motor deficits (moderate)
  • abnormal social interactions
  • excessive grooming and nurturing behavior
• Platelet activation and neuronal damage following a traumatic brain injury
• Reduced gene and protein expression of proteolipid protein-1 (Plp1)²⁶
• Increased expression of proinflammatory cytokines²⁶
  • Interleukin-1β is upregulated
• Lipopolysaccharides induce sex-dependent abnormalities in the inflammatory response and social behavior²⁶
• Signs of hypomyelination²⁶

The STA3GAL5 knockout mouse is a mild manifestation of the STA3GAL5 phenotype.²⁷ More severe forms are associated with developmental disorders, severe hearing, vision, motor, and cognitive disorders, as well as respiratory chain disorders. For more information, see STA3GAL5 In the article Gene candidates without a plausible mechanism of action in relation to ADHD

St3gal5-/-/B4galnt1-/- double-knockout mice lack any ganglioside derivative of LacCer.
Shortly after birth, they develop severe neurodegeneration characterized by impaired axon-glia interactions, weakness in the hind limbs, ataxia, tremors, and heightened inflammatory responses. They die before reaching two months of age.²⁸

3.11. PACAP(-/-) - Mouse¶

Mice lacking pituitary adenylate cyclase-activating polypeptide (PACAP) (PACAP(-/-)) exhibited:²⁹

• Hyperactivity
• Impaired memory for new objects
• Pre-pulse inhibition is impaired

Atomoxetine improved all three symptoms and increased extracellular norepinephrine and dopamine levels in the PFC of PACAP(-/-) mice to a greater extent than in wild-type mice.

3.12. Wheel-Running Mouse¶

Mice bred by selecting those animals that used the running wheel more frequently on their own showed:³⁰³¹

• Hyperactivity in a new environment

• more running, in the form of shorter and faster runs

• Hyperactivity even after a 24-hour acclimatization period in cages without exercise wheels

• D1/D5 receptors with reduced function

• D2/D3/D4 receptors remain unchanged

• Cocaine (dopamine reuptake inhibitor)³¹

  • reduces the average speed, but not the duration of wheel use, in wheel-running mice
  • Unchanged use of the running wheel in the wild-type strain

• GBR 12909 (dopamine reuptake inhibitor)³¹

  • reduces the average speed, but not the duration of wheel use, in wheel-running mice
  • Unchanged use of the running wheel in the wild-type strain

• Ritalin (15 mg/kg and 30 mg/kg)³⁰

  • Reduced wheel use in wheel-running mice
  • Increased wheel use in the wild-type strain

• Apomorphine (non-selective D2 agonist)³⁰

  • A 0.125 mg/kg reduction in wheel use was observed in both wheel-running mice and wild-type mice
  • 0.25 mg/kg and 0.5 mg/kg reduced wheel use more significantly in the wild-type group

• SCH 23390 (selective D1/D5 antagonist)³⁰

  • At concentrations of 0.025, 0.05, and 0.1 mg/kg, wheel use was reduced more significantly in wild-type mice than in Whlrunning mice.

• Raclopride (selective D2 antagonist)³⁰

  • Doses of 0.5, 1, and 2 mg/kg reduced wheel use in wheel-running mice and wild-type mice to a similar extent

• Fluoxetine (SSRI)³¹

  • reduced running speed and duration of wheel use in wheel-running mice and wild-type mice, proportional to baseline activity

3.13. PTCHD1 knockout mouse¶

In the PTCHD1-KO mouse, the PTCHD1 receptors in the thalamus are inactivated.

Male mice with inactivated PTCHD1 exhibited ADHD symptoms:³²

• Distractibility³³
• Problems with Recognition Memory³⁴
  • Atomoxetine reversed this change.³⁴
• Hyperactivity³³³⁴
  • Atomoxetine reversed this change.³⁴
• Impulsivity³⁴
  • Atomoxetine reversed this change.³⁴
• Learning Disabilities³³
• Hypotension³³
• Aggression³³
• Sleep fragmentation³³

In addition, changes in kynurenine metabolism were observed.³⁴

When PTCHD1 was inactivated only in the reticular nucleus of the thalamus, the only findings were elevated levels of³³

• Distractibility
• Hyperactivity
• Sleep Problems

3.14. Neonatal Anoxia Mouse¶

Neonatal anoxia (postnatal oxygen deprivation) increases the risk of ADHD.³⁵³⁶

Symptoms:
Males were more severely affected than females.³⁷

• Hyperactivity
  • in males in open fields³⁸³⁹
  • from Day P20 to P45⁴⁰
  • not increased⁴¹
• Persistent deficits in spatial memory⁴⁰⁴²
• cognitive impairments in task comprehension⁴¹
• Difficulties with sustained attention⁴¹
• Increased impulsivity⁴¹
• Increased compulsivity⁴¹
• increased sensitivity to pain⁴³
  • Responses to nociceptive stimuli vary by gender
• Fear-related behavior in adult males³⁷

Neurophysiological changes:

• Abnormalities in monoamines⁴⁴
• Changes in cell density in the CA1 region of the hippocampus⁴⁰
• Cell loss in the substantia nigra⁴⁵
• Loss of brain volume, particularly ipsilateral, in⁴¹
  • the entire hemisphere
  • cerebral cortex
  • white substance
  • Hippocampus
  • Striatum

Acute anoxia (acute oxygen deprivation) caused:⁴⁴

• Within 20 minutes:
  • Norepinephrine decreases in the cerebellum
  • Dopamine levels decrease in the striatum
  • Elevated levels of 5-hydroxyindoleacetic acid (5-HIAA) in the cortex and cerebellum
• P7 (Day 7)
  • Increased norepinephrine levels in the cerebellum
  • Reduced levels of serotonin (5-HT) and 5-HIAA in the cortex and cerebellum
• P21
  • Increased norepinephrine levels in the hippocampus
  • Increased levels of homovanillic acid (HVA) in the striatum
  • Serotonin levels decrease in the striatum
  • Increased 5-HIAA levels in the striatum and hippocampus
• P60
  • Elevated levels of 3,4-dihydroxyphenylacetic acid (DOPAC) in the striatum
  • and elevated 5-HIAA levels in the striatum

15 minutes of perinatal asphyxia (lack of oxygen during birth) resulted in:⁴⁶

• Tyrosine hydroxylase mRNA levels are elevated in the VTA and substantia nigra
• Elevated levels of DRD1 and DRD2 mRNA in the striatum

A similar mouse model, which simulates the damage caused by oxygen deprivation due to extreme prematurity through repeated episodes of hypoxia, showed:⁴⁷

• Hyperactivity and impulsivity in response to a delayed reward
• no hyperactivity in unfamiliar surroundings
• no inattention
• significant specific loss of dopaminergic neurons (only) in the right VTA

3.15. Cry1Δ11 mice¶

Cry1Δ11 (c. 1717 + 3A > C) mice exhibit ADHD-like symptoms:⁴⁸

• Hyperactivity
• Impulsivity
• Learning deficits
• Memory deficits
• hyperactive cAMP signaling pathway in the nucleus accumbens
• Upregulated c-Fos, localized primarily in dopamine D1 receptor-expressing medium spiny neurons (DRD1-MSNs) in the NAc
• increased neuronal excitability of DRD1-MSNs in the nucleus accumbens
• Unlike the wild-type (WT) CRY1 protein, the CRY1Δ11 protein was mechanistically unable to interact with the Gαs protein and inhibit DRD1 signaling
• The DRD1 antagonist SCH23390 normalized most ADHD-like symptoms

3.16. Pln-/-KO mice¶

At the protein level, phospholamban is found in the reticular thalamic nucleus. This nucleus plays a major role in vital neurological processes, including executive functions and the regulation of sleep rhythms.

Compared to their Pln+/+ littermates, Pln-/- mice show:⁴⁹

• Hyperactivity
• reduced anxiety-related behavior
• Deficits in spatial working memory
• Unaltered object-location memory
• Impaired object recognition memory
• social exploratory behavior / sociability / preference for new social situations: unchanged

In contrast, ablation of phospholamban—restricted to the reticular thalamic nucleus, which did not affect peripheral PLN synthesis in cardiac, skeletal, and smooth muscles—results in:⁴⁹

• Hyperactivity
• Increased impulsivity
• unchanged anxiety behavior
• Unaltered spatial working memory
• Shorter periods of wakefulness
• REM sleep is prolonged, especially in females
• Prolonged non-REM sleep
• Attention level remains unchanged

3.17. Mice with stimulated CaMKII+ neurons in the posterior hypothalamus¶

Chemogenetic activation of CaMKII-positive (CaMKII+) neurons in the posterior hypothalamus resulted in:⁵⁰

• increased locomotor activity
  • Movement speed doubled
  • sudden leaps
  • Hyperkinesia unaffected by clonidine
• increased impulsivity
  • effectively reduced by clonidine
• increased risk-taking behavior
• reduced social interaction
  • unaffected by clonidine
• no increased anxiety
• no increased avoidance behavior

Mice with inhibited CaMKII-positive (CaMKII+) neurons in the posterior hypothalamus exhibited reduced locomotor activity compared to controls.

3.18. SERT-KO Mice on a Western Diet¶

Mice with a deactivated serotonin transporter gene show the following when fed a Western diet (a diet high in saturated fats, cholesterol, and sugar):

• Behaviors reminiscent of ADHD
• significant metabolic disorders
  These abnormalities could be mediated by a disorder in insulin receptor (IR) signaling, which has also been linked to ADHD in adults.⁵¹

3.19. GLUT3-KO mice¶

The GLUT3 gene encodes a glucose transporter that is particularly important for supplying energy to neurons in the brain.

Mice with a homozygously inactivated GLUT3 gene exhibited ADHD symptoms:⁵²⁵³

• Hyperactivity associated with anxiety
  • more pronounced in males than in females
• Motor problems
  • reduced latency until a fall in the Rotorod motor test
• impaired contextual fear conditioning (reduced)
  • more pronounced in females
• impaired spatial memory
  • reduced time spent in the target quadrant during tests of spatial cognitive memory in the water maze
• Impulsivity
  • increased sociability, especially when it comes to new things
  • more pronounced in females

In heterozygous GLUT-3+/- mice, a ketogenic diet had sex-specific effects:⁵⁴

• Only male GLUT-3+/- mice showed the following at 5 months of age:
  • reduced glucose/lactate concentrations in the cerebrospinal fluid, with unchanged GLUT-1, MCT2, glucose uptake, or ATP levels in the brain
  • increased glucose uptake in the brain in response to exogenous insulin-induced hypoglycemia
  • Lower plasma and CSF ketone (β-hydroxybutyrate) levels and higher Glut3 levels in the brain compared to females increased the vulnerability of males
  • increased levels of synaptic proteins (neuroligin-4 and SAPAP1) associated with spontaneous excitatory postsynaptic activity, which, in an age-dependent manner (between 4 and 24 months of age), reduced glucose levels in the hippocampus and increased the deposition of amyloid β1-40 in the brain
• A ketogenic diet
  • alleviated the seizures caused by increased cortical excitation
  • improved social interaction
  • did not alter vocalization or cognitive deficits

3.20. TSC2-KO mice¶

TSC2-KO mice exhibit tuberous sclerosis-associated neuropsychiatric disorders as well as epilepsy. Female TSC2-KO mice exhibited more severe manifestations of hyperactivity and cognitive disorders. TSC-associated disorders are thought to be caused by hyperactivation of the Mechanistic Target of Rapamycin Complex 1 (mTORC1). mTORC1 inhibitors improve nearly all TSC symptoms. The mTORC1 inhibitor sirolimus improved TSC-associated neuropsychiatric disorders in TSC2-KO mice by modulating steroid levels in the brain and regulating E2/ERα-dependent transcriptional activation. Sirolimus may potentially be useful for the treatment of TSC-associated neuropsychiatric disorders as well as diseases caused by sex-specific differences and steroid levels.⁵⁵

3.21. Lister hooded rat (LHR)¶

Lister-Hooded rats (LHR), an old, overbred strain frequently used in research on autistic epilepsy, showed more compared to SHR (the most commonly used animal model for ADHD) and Wistar (a control animal)⁵⁶

• Hyperactivity
• Impulsivity
• Inattention

According to another source, only LHR mice raised in social isolation exhibited hyperactivity, as did Wistar mice raised in isolation; Sprague-Dawley mice raised in isolation did not exhibit hyperactivity.⁵⁷

Compared to SHR and Wistar rats, LHR rats showed reduced expression of ADHD candidate genes:⁵⁶

• CDH13
• DRD5
• FOXP2
• MAOA
• SEMA6D
• SLC9A9
• ST3GAL3

as well as reduced tyrosine hydroxylase protein expression.

Female Lister-Hooded (LH) rats are more prone to self-administering cannabinoids than males.⁵⁸

LHRs showed increased expression in the prelimbic region of the mPFC compared to SHRs and Wistars:⁵⁶

• c-Fos
• Synapsin I

Atomoxetine and guanfacine improved ADHD symptoms in LHR.⁵⁶
Atomoxetine improved spatial memory in LHR and increased cell proliferation in the subgranular zone.⁵⁹
Methylphenidate (2 × 4 mg/kg/day, intraperitoneal) caused⁶⁰

• mild hyperactivity
• no stereotypical behavior
• Exploration of new items remains unchanged
• Social behavior remains unchanged after weaning
• Dopamine levels in the striatum remain unchanged

D-amphetamine at LHR⁶¹

• increased the preference for delayed, larger rewards when a light stimulus was illuminated during the delay
• reduced the preference for delayed, larger rewards when the light was turned off at the moment of choice

An enriched environment improved the symptoms of LHR.⁶²

Nicotine can improve attention and alertness in ADHD. A genetic knockout of the α7 nicotinic acetylcholine receptor (nAChR) leads to attention deficits. The partial α7-nAChR agonist enceniclin (formerly EVP-6124) improves memory performance in rodents and humans.
Female Lister-Hooded rats were divided into 4 groups based on their vigilance and accuracy (selective attention) in the 5C-CPT.
The quarter with the lowest performance showed 0.3 mg/kg of enceniclin:⁶³

• increases selective attention
• Increased vigilance (even at 1 mg/kg)
• Reduced impulsivity (probability of false alarms)

The most potent quartile was observed at 1 mg/kg of enceniclin:

• reduced selective attention
• Reduced vigilance

The Stop Signal Response Time (SSRT) paradigm measures the ability to stop a motor response after it has been initiated. In LHR, the SSRT was influenced by:⁶⁴

• Atomoxetine (NET reuptake inhibitor): Accelerates SSRT, improves accuracy on “Go” trials
• Citalopram (SERT reuptake inhibitor): Slows “Go” reaction time, reduces “Go” accuracy (at the highest dose of 1 mg/kg)
• GBR-12909 (selective DAT reuptake inhibitor): Accelerated “Go” reaction time; reduced “Go” and “Stop” accuracy
• Guanfacine (alpha-2-adrenoceptor agonist): worsened all key stop-and-go test measures (at the highest dose of 0.3 mg/kg)

In LHR rats, a 14-day tryptophan-free diet affected locomotor activity, whereas no differences were observed in Wistar rats.⁶⁵

Nicotine-naive LHR mice do not show an increased dopamine response in the nucleus accumbens following nicotine pretreatment, unlike Sprague-Dawley mice, which are not ADHD model animals.⁶⁶
Acute nicotine administration did not affect prepulse inhibition in the LHR. Chronic nicotine administration caused a marked deficit in prepulse inhibition and a significant increase in locomotor activity and [3H]nicotine binding.⁶⁷

All in all, it seems to us that the older studies on LHR do not paint a picture of a typical response to stimulants.

3.22. IL-4 mouse¶

IL-4, administered during the second week of life, increased hyperactivity and impulsivity in mice. Allergic asthma in early life had the same effect.⁶⁸⁶⁹

3.23. Slitrk2 knockout mouse¶

Slitrk2-KO mice show:⁷⁰

• Hyperactivity
• altered vestibular function
• serotonergic dysregulation.

In Slitrk2-KO mice, levels of the dopamine metabolite homovanillic acid were significantly elevated in the hippocampus (+24%), while no change was observed in the striatum or nucleus accumbens. No changes were observed in dopamine levels or its metabolites in the nucleus accumbens, where dopaminergic dysregulation can trigger hyperactivity.
Methylphenidate did not alleviate the hyperactivity.⁷⁰
Norepinephrine levels remained unchanged in the various regions of the brain.

3.24. Roman High- (RHA) and Low-Avoidance (RLA) Rats¶

Roman High- (RHA) and Low-Avoidance (RLA) rats are animal models for the different phenotypes of impulsivity.⁷¹

3.25. Congenic wiggling rat (Wig rat)¶

Wig rats were developed by selecting spontaneously hyperactive Long-Evans Cinnamon (LEC) rats and transferring genes from the LEC to the Wistar King-Aptekman/Hokkaido (WKAH) strain.⁷²
Wig rats showed:

• Hyperactivity⁷³
  • Inherited in an autosomal recessive pattern⁷²
  • Motor activity in 12- to 14-week-old Wig rats was significantly increased during the day and very significantly increased at night⁷²
  • Mobility significantly increased in the open-field test⁷²
  • Standing up reduces, compared to the control group⁷²
• Impulsivity⁷³⁷²
• Working memory problems⁷³⁷²
• Inattention—allegedly none⁶
• Y-Maze Test⁷²
  • Significantly impairs spontaneous switching behavior
  • With the total number of admissions to the arm remaining unchanged
• The water maze test could not be conducted because the Wig rats panicked upon contact with water and nearly drowned⁷²

Congenic WIG rats also showed:⁷³

• A subcutaneous injection of 4 mg/kg of methamphetamine exacerbated the hyperactivity
• Low levels of tyrosine hydroxylase in the ventral midbrain
• Increased expression of the adenosine A2a receptor in the dorsal striatum
• Increased expression of macrophage migration inhibitory factor in the frontal cortex, the ventral striatum, and the midbrain
• Increased expression of calbindin 2 in the dorsal and ventral midbrain
• Reduced expression of the GABA transporter gene in all brain regions
• Reduced expression of sterol transporter protein 2 in all regions of the brain
• Increased expression of the DAT gene in the dorsal midbrain
• Reduced expression of the DAT gene in the ventral midbrain

3.26. Thyroid Receptor Beta Mutant Mouse¶

This mouse is designed to demonstrate:⁶

• Hyperactivity
• Impulsivity
• Inattention

3.27. CdK5-dysregulated mouse¶

The CdK5-dysregulated mouse is intended to demonstrate:⁶

• Hyperactivity
• Impulsivity
• No inattention

3.28. Med23 knockout mouse¶

Med23-KO mice showed⁷⁴

• Hyperactivity
• Impulsivity
• Inattention
• Impaired sensory filtering
• Impaired working memory
• MPH addressed these shortcomings
• Severe hypoplasia of the dentate gyrus with malformation of the dendritic tree and spines, as well as impaired short-term synaptic plasticity.
• MPH partially restored impaired synaptic plasticity in an N-methyl-D-aspartate (NMDA) receptor-dependent manner

3.29. Ovalbumin-induced allergy mouse¶

Mice in which allergies were induced by ovalbumin showed:⁷⁵

• Impaired attention
  • a significantly reduced level of visual, non-selective, and non-sustained attention
• reduced motor activity
• Impaired social behavior
  • less interest in interacting with other mice
• Communication is impaired
• Increased anxiety
• Increased depression

3.30. CERS6KO mice¶

CERS6KO mice, which lack CERS6, show:⁷⁶

• Hyperactivity
• Restlessness
• Nervousness
• Increased level of physical activity
• Increased standing activity
• Increased average running speed
• Increased total duration of the movement
• Increased exploration activity in the open field
• Unchanged exploration activity in new environments
• Unchanged immobility
• Unchanged rotational behavior

3.31. CFTR-knockout fish¶

Cystic fibrosis is associated with mutations in the CFTR gene⁷⁷, which has been identified as a candidate gene for ADHD.⁷⁸⁷⁹⁸⁰
CTFR-KO zebrafish exhibit ADHD symptoms such as hyperactivity, impulsivity, and attention problems.⁸¹

CFTR (CNFTR) is a candidate gene for ADHD.⁷⁸ For more information, see CFTR, the gene encoding the ciliary neurotrophic factor receptor (CNFTR) In the article “ Monogenic Causes of ADHD.”

3.32. Dogs with ADHD¶

A study of dogs exhibiting ADHD-like behavior found relatively low levels of dopamine and serotonin in their blood.⁸²

3.33. Drosophila (fruit fly)¶

Research on Drosophila has shown that gene variants determine the behavior of Drosophila, for example, in response to unpleasant bursts of air.
Drosophila that exhibited a particularly prolonged hyperactive response to bursts of air had a specific mutation in the dopamine transporter gene, which is one of the most important candidate genes for ADHD.⁸³ When these Drosophila were treated with cocaine, they calmed down more quickly.
The dopamine D1 receptor was essential for learning behavior in Drosophila. Drosophila with a D1 receptor that had been artificially inactivated (throughout the entire brain) were unable to learn that a specific odor served as a warning signal for a puff of air.⁸⁴
When the D1 receptor gene was repaired exclusively in the “Central Complex” region of the brain, the Drosophila were no longer hyperactive but were still unable to learn. If, on the other hand, the D1 receptor gene was restored only in the “mushroom body” region of the brain, the ability to learn was restored, while the hyperactivity persisted.⁸³

A Drosophila strain bred for sleep problems exhibited both significant hyperactivity and increased sensitivity to environmental stimuli after 60 generations.⁸⁵

77% of human disease genes have homologs in Drosophila.⁸⁶ Although the evolutionary branches of Drosophila and humans diverged 700 million years ago, the Drosophila brain, like that of vertebrates, is organized into three parts (forebrain, midbrain, and hindbrain) and uses the same key neurotransmitters (dopamine, glutamate, GABA, homologs of epinephrine, norepinephrine, and serotonin), as well as the corresponding enzymes, transporters, and receptors.⁸⁷⁸⁸

Drosophila Exposed to Imidacloprid

Imidacloprid is a neonicotinoid that acts as an insecticide.
Imidacloprid is suspected of causing ADHD.⁸⁹
Even the smallest amounts can cause damage to the cerebellum, which, when dysfunctional, is associated with ADHD.⁹⁰

Drosophila melanogaster were exposed to food containing imidacloprid for 7 days.
Their descendants showed:⁹¹

• Hyperactivity
• Aggressiveness
• changes in social interaction
• repetitive movements
• Anxiety

When the offspring were exposed to food containing lutein nanoparticles for 24 hours, this reversed the behavioral parameters mentioned above.
A diet containing lutein-rich nanoparticles also protected markers of oxidative stress and cell viability and prevented a decrease in Nrf2 and Shank3 immunoreactivity.⁹¹
Lutein works

• anti-inflammatory
• antioxidant
• neuroprotective

When the mothers were fed nanoparticles containing lutein prior to fertilization, this prevented the development of imidacloprid-induced ADHD symptoms in their offspring.⁹²