ADHD animal models with unknown dopamine alteration

In this paper, we collect animal models of ADHD in which the way in which dopamine levels are altered has not yet been revealed to us.

• 3.1. 39.XY*O–Mouse (DHEA deficiency) (dopamine unchanged)
• 3.2. GIT1-KO mouse (dopamine effect reduced?)
• 3.3. ATXN7 Overexpressed mouse
• 3.4. Grin1 mouse
• 3.5. AGCYAP1-KO mouse
• 3.6. Neurokinin-1 (Substance P, Tachikinin) Receptor-KO-Mouse (TACR1-KO-Mouse)
• 3.7. Guanylylcyclase-C-KO mouse (GC-C-KO mouse)
• 3.8. GAT1-KO mouse
• 3.9. TR-beta 1 transgenic mouse
• 3.10. FEZ1-KO mouse
• 3.11. STA3GAL5(-/-) - Mouse
• 3.12. PACAP(-/-) - Mouse
• 3.13. Wheelrunning mouse
• 3.14. PTCHD1-KO mouse
• 3.15. Neonatal anoxia mouse
• 3.16. Cry1Δ11 mice
• 3.17. Pln-/-KO mice
• 3.18. Mice with stimulated CaMKII+ neurons in the posterior hypothalamus
• 3.19. SERT KO mice with Western Diet
• 3.20. GLUT3-KO mice
• 3.21. TSC2-KO mice
• 3.22. Prenatal nicotine exposure mouse
• 3.23. Lister hooded rat (LHR)
• 3.24. IL-4 mouse
• 3.25. Slitrk2-KO mouse
• 3.26. Roman High- (RHA) and Low-Avoidance (RLA) rats
• 3.27. Congenic wiggling rat (Wig rat)
• 3.28. Thyroid receptor beta mutant mouse
• 3.29. NK1-KO mouse
• 3.30. CdK5-dysregulated mouse
• 3.31. Med23-KO mouse
• 3.32. Ovalbumin-induced allergy mouse
• 3.33. CERS6KO mice
• 3.34. CFTR-KO fish
• 3.35. Dogs with ADHD
• 3.36. Drosophila (fruit fly)

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 to DHEA.

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

• increased reactivity to a new environment¹
• Hyperactivity in the active phase¹
• Inattention²
• increased emotional reactivity¹
• increased water consumption (but not food)¹
• increased motivation²
• no difference in social dominance¹
• significantly lower DHEA serum levels¹
• equivalent corticosterone levels¹
• Increased serotonin²
  • in the striatum
  • in the hippocampus
• Reduced serotonin turnover²
  • in the striatum
  • in the hippocampus
• Noradrenaline turnover reduced²
  • in the striatum
• MOPEG decreases in the striatum²
• Dopamine unchanged in PFC, striatum, hippocampus, thalamus, cerebellum²

We find it interesting that brain dopamine levels are unchanged, although STS can convert dopamine sulfate into dopamine. This could be an indication that dopamine synthesis by STS does not play a relevant role in the brain.

The STS gene is a gene candidate for ADHD.

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

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

• Hyperactivity
  • remediable with amphetamine and methylphenidate
• Learning disorders
• Memory loss
• no impulsiveness⁶
• no inattention⁶

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

GIT1-KO mice showed the following characteristics compared to wild-type mice⁴

• a reduced glial GABA intensity
• a weakening of the tonic current from the cerebellar granule cells

3.3. ATXN7 Overexpressed mouse¶

The ATXN7 Overexpressed mice (ATXN7-OE) show

• Hyperactivity
• Impulsiveness
• no inattention

This corresponds to the ADHD-HI subtype.
The ataxin 7 gene (ATXN7) correlates with hyperactivity. ATXN7-OE mice have overexpression of the Atxn7 gene and protein in the PFC and striatum. Atomoxetine (3 mg/kg, intraperitoneal) decreases ADHD-HI-like behavior and ATXN7 gene expression in 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 required for NMDA receptor function. Grin2B may be associated with ADHD. Grin1 mice show:

• Hyperactivity⁹
• Novelty seeking⁹
• Reduced social interaction⁹
• Anxiety¹⁰

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

Hyperactivity improved with high-dose methylphenidate. While c-FOS was very low in the prelimbic cortex and striatum of control mice and increased by MPH, c-FOS was high in the prelimbic cortex of GRIN1Rgsc174 ⁄ + mice and was reduced by MPH (at very high doses). Grin1Rgsc174 ⁄ + mice further showed increased phosphorylation of the protein ERK2 in the nucleus accumbens, which barely changed even after an extreme MPH dose (30 mg/kg). The authors concluded that the behavioral symptoms of the GRIN1 mouse were due to NMDA receptor dysfunction in the relevant brain regions, and that the effect of MPH in the GRIN1 mouse was not specifically mediated via the DAT, but via other receptors or influences, since the DAT should have shown an effect even at much lower doses.¹⁰ The authors also point to the altered glutamatergic neurotransmission in SHR. SHR do not react 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 generated in the pituitary gland. Mice lacking the ADXAP1 gene (Adcyap1(-/-)) show increased novelty seeking and hyperactivity. One study found sensory-motor gating deficits in them in the form of prepulse inhibition (PPI) deficits. Amphetamine was able to normalize PPI and hyperactivity. This occurred via serotonin-1A (5-HT(1A)) receptor signaling. Wild-type mice also developed hyperactivity in response to the 5-HT(1A) agonist 8-hydroxy-2-(di-n-propylamino)tetralin, which was also reversed by AMP. In addition, increased c-Fos-positive neurons were found in the PFC of AGCYAP1-KO mice treated with AMP, indicating increased inhibitory control by prefrontal neurons.¹¹

3.6. Neurokinin-1 (Substance P, Tachikinin) Receptor-KO-Mouse (TACR1-KO-Mouse)¶

The TACR1-KO mouse is another rodent model for ADHD.¹²

Virtually all dopaminergic neurons of the substantia nigra pars compacta and many of the substantia nigra pars reticulata contain neurokinin-1 receptors.¹³ Substance P mediates its effect via postsynaptic heteroreceptors as well as via presynaptic autoreceptors. Substance P has an excitatory effect and modulates the inhibitory effect of GABA in the substantia nigra.
Substance P is involved in the regulation of dopamine release in the striatum.¹⁴¹⁵ The effect of substance P on dopaminergic transmission appears to be mediated by a nigro-thalamo-cortico-striatal loop.¹⁶
Substance P increases dopamine in the nucleus accumbens, but not in the neostriatum.¹⁷
TACR1 is associated with dopaminergic activity in the striatum.¹⁸ TACR1 mediates the action of the protein kinase C pathway in the downregulation of DAT and NET. The effect appears to be mediated via NET rather than DAT.¹⁹

We believe that these data may be indicative of reduced dopamine levels in TACR1-KO mice.

3.7. Guanylylcyclase-C-KO mouse (GC-C-KO mouse)¶

Guanylyl cyclase-C (GC-C) is a membrane receptor and is found together 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 glutamate and acetylcholine receptor-mediated excitatory responses via guanosine 3’,5’-monophosphate-dependent protein kinase (PKG) activity, which affects dopaminergic cells.

GC-C-KO mice show:

• Hyperactivity (?)
  • in familiar and new environments²⁰
  • is canceled by
    • systemic AMP injection²⁰
    • GMP-dependent protein kinase agonist infusion into the VTA²⁰
  • Another study found no hyperactivity²¹
• Attention deficit in the Go/No-Go test.²⁰
  • is canceled by
    • systemic AMP injection²⁰
    • GMP-dependent protein kinase agonist infusion into the VTA²⁰
• extensive investigation of new odors²⁰
• Recognition of new objects impairs²¹
• tactile shock reduces²¹
• acoustic shock unchanged²¹
• increased latency during training trials in the Morris water maze only in females²¹
  • not for spatial learning attempts with a hidden platform

3.8. GAT1-KO mouse¶

Tonic GABA inhibits the release of dopamine in the striatum (of the mouse) via GABA-A and GABA-B receptors. Only a few GABAergic synapses are present at the dopamine axons. Therefore, the tonic inhibition of dopamine release by striatal GABA is probably mediated by extrasynaptic effects of extracellular GABA on receptors presumably located on dopamine axons. GABA therefore shows extrasynaptic effects on other neurons.
Gamma-aminobutyric acid transporters of subtype 1 and subtype 3 reuptake GABA. If the GABA transporters GAT1 or GAT3 are reduced or switched off, this increases the extracellular GABA and thus reduces the release of dopamine in the dorsal striatum, but not in the nucleus accumbens.²²²³

The two isoforms of the GAT in the striatum are:

• GAT-1 (Slc6a1)
  • common in axons of GABAergic neurons
  • in striatal astrocytes
  • in DA midbrain neurons
  • on striatal DA axons
• GAT-3 (Slc6a11)
  • moderately expressed
  • especially occurring on (striatal) astrocytes
    • Dysregulation of GAT-3 on striatal astrocytes causes profound changes in SPN activity and striatal-driven behavior through decreased extracellular dopamine²⁴
  • in DA midbrain neurons
  • on striatal DA axons

(GAT1)-KO mice (GAT-1-/- mice) show typical ADHD symptoms:²⁵²⁶

• Hyperactivity
  • AMP and MPH reduce these
• motor problems
  • Ataxia, characterized by deficiencies in motor coordination and balance
• Attention problems
  • Impairment of attentional focus in an “incentive runway test”
• Impulsiveness in an incentive test for passive avoidance
• Memory problems
  • Deficits in spatial reference memory

3.9. TR-beta 1 transgenic mouse¶

Carries a mutated human thyroid receptor TRb 1 gene.

TRbeta-transgenic mice²⁷

• are euthyroid except for a short period during postnatal development (= normal thyroid hormone levels of triiodothyronine (T3) and thyroxine (T4)).
• show until adulthood
  • Changes in the dopaminergic system (increased dopamine turnover)
  • ADHD symptoms
  • paradoxical reaction to MPH

Thus, like the vast majority of children with ADHD, the TRbeta transgenic mice show ADHD symptoms without measurable thyroid abnormalities. It is possible that even transient disorders of developmental thyroid homeostasis cause long-lasting behavioral and cognitive consequences, including the development of the full spectrum of ADHD symptoms.

Symptoms:

• Hyperactivity
• Impulsiveness
• Inattention
• All symptoms
  • Are reduced by methylphenidate
  • As with ADHD, are dynamic and react sensitively to changing environmental conditions, stress and reinforcement

3.10. FEZ1-KO mouse¶

The Fez1 gene (fasciculation and elongation protein zeta-1) is specifically expressed in the nervous system and is involved in neurodevelopment.
FEZ1 knockout mice show:²⁸

• Hyperactivity²⁹
• Impulsiveness
• Tyrosine hydroxylase expression reduced in midbrain and brainstem
• Dopamine and noradrenaline levels and their metabolites in the nucleus accumbens and PFC reduced
• MPH and guanfacine caused
  • Hyperactivity and impulsivity improved
  • Dopamine and noradrenaline levels restored in the nucleus accumbens and PFC
  • Tyrosine hydroxylase expression increased

The FEZ1 gene is specifically expressed in the nervous system and is most strongly expressed during neurodevelopment. FEZ1 is involved in various processes of neurodevelopment, such as:²⁸

• Neurite extension
• dendritic arborization
• axonal transport
• neuronal migration

3.11. STA3GAL5(-/-) - Mouse¶

St3gal5-/- mice. In contrast to B4galnt1-/- mice, the clinical abnormalities only partially regress in these mutants, which could be due to the compensatory synthesis of the 0-series gangliosides GD1α and GM1b. However, the
St3gal5-/- mice lack the most important CNS gangliosides GM3, GM1, GD1a, GD3, GT1b and GQ1b
St3gal5-/- mice show:³⁰

• motor hyperactivity
• Impulsiveness
• Inattention³¹
• increased insulin sensitivity³²
• autistic behavior³³
  • conditioned taste aversion impaired in an inhibitory learning task
  • fear-like behavior in the field
  • motor deficits (moderate)
  • abnormal social interactions
  • excessive grooming and rearing behavior
• Platelet activation and neuronal damage after traumatic brain injury
• Proteolipid protein-1 (Plp1) gene and protein expression reduced³³
• proinflammatory cytokine expression increased³³
  • Interleukin1β is upregulated
• Lipopolysaccharides induce sex-dependent abnormalities in inflammatory response and social behavior³³
• Signs of hypomyelination³³

The STA3GAL5-KO mouse is a mild form of the STA3GAL5 disorder.³⁴ More severe forms are associated with developmental disorders, severe hearing, visual, motor and cognitive impairments and respiratory chain disorders. More on this at STA3GAL5 In the article Gene candidates without a plausible pathway in relation to ADHD

St3gal5-/-/B4galnt1-/- mice with double knockout lack any ganglioside derivative of LacCer.
Soon after birth, they develop severe neurodegeneration with impaired axon-glia interactions, weakness of the hind limbs, ataxia, tremor and increased inflammatory reactions. They die before the age of two months.³⁵

3.12. PACAP(-/-) - Mouse¶

Mice with pituitary adenylate cyclase-activating polypeptide (PACAP) deficiency (PACAP(-/-)):³⁶

• Hyperactivity
• Memory for new objects impaired
• Pre-pulse inhibition impaired

Atomoxetine improved all 3 symptoms and increased extracellular norepinephrine and dopamine in the PFC of PACAP(-/-) mice more than in wild-type mice.

3.13. Wheelrunning mouse¶

Mice that were bred by selecting those animals with a higher voluntary use of the running wheel:³⁷³⁸

• Hyperactivity in a new environment

• more wheel use in the form of shorter and faster runs

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

• D1/D5 receptors with reduced function

• D2/D3/D4 receptors unchanged

• Cocaine (dopamine reuptake blocker)³⁸

  • reduces average speed, but not duration of wheel use with wheel running mice
  • unchanged impeller use with wild type

• GBR 12909 (dopamine reuptake blocker)³⁸

  • reduces average speed, but not duration of wheel use with wheel running mice
  • unchanged impeller use with wild type

• Ritalin (15 mg/kg and 30 mg/kg)³⁷

  • reduced wheel usage with wheel running mice
  • increased wheel utilization with wild type

• Apomorphine (non-selective D2 agonist)³⁷

  • 0.125 mg/kg reduced wheel use in wheel-running mice and wild-type mice alike
  • 0.25 mg/kg and 0.5 mg/kg reduced impeller use in the wild type more strongly

• SCH 23390 (selective D1/D5 antagonist)³⁷

  • 0.025, 0.05 and 0.1 mg/kg reduced running wheel use in wild type more than in running mice

• Racloprid (selective D2 antagonist)³⁷

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

• Fluoxetine (SSRI)³⁸

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

3.14. PTCHD1-KO mouse¶

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

Male mice with deactivated PTCHD1 showed:

• Distractibility³⁹
• Problems with recognition memory⁴⁰
  • Atomoxetine eliminated this change.⁴⁰
• Hyperactivity³⁹⁴⁰
  • Atomoxetine eliminated this change.⁴⁰
• Impulsiveness⁴⁰
  • Atomoxetine eliminated this change.⁴⁰
• Learning disorders³⁹
• Hypotension³⁹
• Aggression³⁹
• Sleep fragmentation³⁹

There were also changes in the kynurenine metabolism.⁴⁰

When PTCHD1 was only deactivated in the reticular nucleus of the thalamus, only increased levels of³⁹

• Distractibility
• Hyperactivity
• Sleep problems

3.15. Neonatal anoxia mouse¶

Neonatal anoxia (postnatal lack of oxygen) increases the risk of ADHD.⁴¹⁴²

Symptoms:
Males were more severely affected than females.⁴³

• Hyperactivity
  • for males in the open field⁴⁴⁴⁵
  • from day P20 to P45⁴⁶
  • not increased⁴⁷
• Permanent deficits in spatial memory⁴⁶⁴⁸
• cognitive impairments during task acquisition⁴⁷
• Deficits in sustained attention⁴⁷
• Increased impulsivity⁴⁷
• Compulsiveness increased⁴⁷
• increased sensation of pain⁴⁹
  • Gender-specific reactions depending on the nociceptive stimulus
• Fear behavior in adult males⁴³

Neurophysiological changes:

• Anomalies with monoamines⁵⁰
• Changed cell density in the CA1 hippocampus⁴⁶
• Cell loss in substantia nigra⁵¹
• Loss of brain volume, especially ipsilateral, in⁴⁷
  • entire hemisphere
  • Cerebral cortex
  • white substance
  • Hippocampus
  • Striatum

Acute anoxia (acute lack of oxygen):⁵⁰

• Within 20 minutes:
  • Noradrenaline reduced in the cerebellum
  • Dopamine reduced in the striatum
  • 5-Hydroxyindoleacetic acid (5-HIAA) increased in the cortex and cerebellum
• P7 (7th day)
  • Noradrenaline increase in the cerebellum
  • Serotonin (5-HT) and 5-HIAA reduced in the cortex and cerebellum
• P21
  • Noradrenaline increase in the hippocampus
  • Increase in homovanillic acid (HVA) in the striatum
  • Serotonin decreases in the striatum
  • 5-HIAA increase in striatum and hippocampus
• P60
  • 3,4-Dihydroxyphenylacetic acid (DOPAC) increased in striatum
  • and 5-HIAA levels increased in the striatum

15 minutes caused perinatal asphyxia (lack of oxygen during birth):⁵²

• Tyrosine hydroxylase mRNA levels increased in VTA and substantia nigra
• DRD1 and DRD2 mRNA increased in the striatum

A similar mouse model, which simulates the damage of oxygen deprivation caused by extreme premature birth through repeated hypoxia, showed⁵³

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

3.16. Cry1Δ11 mice¶

Cry1Δ11 (c. 1717 + 3A > C) mice show ADHD-like symptoms:⁵⁴

• Hyperactivity
• Impulsiveness
• Learning deficits
• Memory deficits
• hyperactive cAMP signaling pathway in the nucleus accumbens
• upregulated c-Fos, mainly localized in dopamine D1 receptor-expressing medium spiny neurons (DRD1-MSNs) in the NAc
• increased neuronal excitability of DRD1-MSNs in the nucleus accumbens
• the CRY1Δ11 protein, unlike the WT CRY1 protein, could not mechanistically interact with the Gαs protein and inhibit DRD1 signaling
• the DRD1 antagonist SCH23390 normalized most ADHD-like symptoms

3.17. Pln-/-KO mice¶

Phospholamban is found at the protein level in the reticular nucleus of the thalamus. This has a major influence on vital neurological processes, including executive functions and the generation of sleep rhythms.

Pln-/- mice exhibit a higher number of littermates compared to their Pln+/+ littermates:⁵⁵

• Hyperactivity
• reduced anxiety behavior
• Deficits in spatial working memory
• unchanged object localization memory
• impaired object recognition memory
• social exploration behavior / sociability / preference for new social territory unchanged

In contrast, ablation of phospholamban limited to the reticular nucleus of the thalamus, which did not affect peripheral PLN synthesis in cardiac muscle, skeletal muscle and smooth muscle:⁵⁵

• Hyperactivity
• Increased impulsivity
• unchanged anxiety behavior
• unchanged spatial working memory
• Waking phases shortened
• REM sleep prolonged, especially in females
• non-REM sleep extended
• Attention unchanged

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

Chemogenetic activation of CaMKII-positive (CaMKII+) neurons in the posterior hypothalamus:⁵⁶

• increased locomotor activity
  • Movement speed doubled
  • sudden leaps
  • Hypermotor activity unaffected by clonidine
• increased impulsiveness
  • effectively reduced by clonidine
• increased risk behavior
• reduced social interaction
  • unaffected by clonidine
• no increased anxiety
• no increased avoidance behavior

Mice with inhibition of CaMKII-positive (CaMKII+) neurons in the posterior hypothalamus showed reduced locomotor function compared to controls.

3.19. SERT KO mice with Western Diet¶

Mice with a deactivated serotonin transporter gene exhibit a high serotonin response when fed a Western diet (“Western diet” with a high proportion of saturated fats, cholesterol and sugar):

• Behaviors reminiscent of ADHD
• significant metabolic disorders
  These abnormalities could be mediated by a disorder of insulin receptor (IR) signaling, which is also associated with ADHD in adults.⁵⁷

3.20. 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 homozygous inactivated GLUT3 gene showed ADHD symptoms:⁵⁸⁵⁹

• Hyperactivity with anxiety
  • more pronounced in males than in females
• Motor problems
  • reduced latency to fall in the motorized rotorod test
• disturbed contextual fear conditioning (reduced)
  • more pronounced in females
• impaired spatial memory
  • reduced time in the target quadrant in tests of spatial cognitive memory in the water maze
• Impulsiveness
  • increased sociability, especially with new things
  • more pronounced in females

In heterozygous GLUT-3+/- mice, a ketogenic diet had a sex-specific effect:⁶⁰

• Only male GLUT-3+/- mice showed at the age of 5 months:
  • reduced glucose/lactate concentrations in the CSF, with unchanged GLUT-1, MCT2, glucose uptake or ATP values in the brain
  • increased glucose uptake in the brain to exogenous insulin-induced hypoglycemia
  • lower plasma CSF ketones (β-hydroxybutyrate) and higher Glut3 in the brain than females increased the vulnerability of males
  • increased synaptic proteins (Neuroligin4 and SAPAP1) with spontaneous excitatory postsynaptic activity that reduced hippocampal glucose levels and increased brain amyloid β1-40 deposition in an age-dependent manner (from 4 to 24 months of age)
• A ketogenic diet
  • alleviated the seizures caused by increased cortical arousal
  • improved sociability
  • did not change the vocalization and cognitive deficits

3.21. TSC2-KO mice¶

TSC2-KO mice show tuberosclerosis-associated neuropsychiatric disorders and epilepsy. TSC2-KO mice showed more severe expressions of hyperactivity and cognitive disorders in females. TSC-associated disorders are thought to be caused by hyperactivation of the Mechanistic Target of Rapamycin Complex 1 (mTORC1). mTORC1 inhibitors ameliorate almost all TSC symptoms. The mTORC1 inhibitor sirolimus ameliorated TSC-associated neuropsychiatric disorders in TSC2-KO mice by modulating brain steroid levels and regulating E2/ERα-dependent transcriptional activation. Potentially, sirolimus could be useful for the treatment of TSC-associated neuropsychiatric disorders as well as diseases caused by sex differences and steroid levels.⁶¹

3.22. Prenatal nicotine exposure mouse¶

Mice exposed to nicotine prenatally show increased ADHD symptoms⁶² such as

• Hyperactivity^{6364656667686970}
  • even if raised by other mothers⁷¹
  • epigenetically heritable⁶⁹
• Impulsiveness⁷²
• Attention problems⁷²⁷³
• Aggressiveness⁶⁷
• Impaired working memory⁷³
• Pre-pulse inhibition impaired⁷³
• Learning problems⁶⁸

Methylphenidate improves behavior and neuroplasticity in these mice.⁷⁴
This is attributed in part to an involvement of AMPA receptor subunit composition and synaptic spine morphology in the hippocampus in ADHD.⁷⁵

Neurophysiologically, mice exposed to nicotine prenatally show

• reduced dopamine levels in the mPFC⁷⁶
• reduced noradrenaline turnover in the PFC in adulthood⁷³.
• increased neuroinflammation⁷⁷
• increased reactive oxygen species (ROS)⁷⁷
• Blood-brain barrier impaired⁷⁸

3.23. Lister hooded rat (LHR)¶

Lister hooded rats (LHR), an old, outbred breed commonly used to study autistic epilepsy, showed more⁷⁹

• Hyperactivity
• Impulsiveness
• Inattention

According to another source, only LHR raised in social isolation showed hyperactivity, as did Wistar raised in isolation, while Sprague-Dawley raised in isolation showed no hyperactivity.⁸⁰

LHR showed reduced expression of ADHD candidate genes compared to SHR and Wistar:⁷⁹

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

and reduced tyrosine hydroxylase protein expression.

Female Lister-Hooded (LH) rats are more susceptible to cannabinoid self-administration than males.⁸¹

LHR showed increased expression in the prelimbic region of the mPFC compared to SHR and Wistar from⁷⁹

• c-Fos
• Synapsin I

Atomoxetine and guanfacine improved ADHD symptoms in LHR.⁷⁹
Atomoxetine improved spatial memory in LHR and increased cell proliferation in the subgranular zone.⁸²
Methylphenidate (2 x 4 mg/kg/day, intraperitoneal) induced⁸³

• mild hyperactivity
• no stereotypical behavior
• Exploration of new items unchanged
• social behavior unchanged after weaning
• Dopamine in the striatum unchanged

D-amphetamine at LHR⁸⁴

• improved the preference for delayed, larger rewards when a stimulus light was illuminated during the delay
• worsened the preference for delayed, larger rewards if the light was extinguished at the moment of choice

Enriched environment improved the symptoms of LHR.⁸⁵

Nicotine can improve attention and vigilance in ADHD. Genetic knockout of the α7-nicotinic acetylcholine receptor (nAChR) leads to attention deficits. The partial α7-NAChR agonist encenicline (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 weakest performing quarter showed encenicline at 0.3 mg/kg:⁸⁶

• increased selective attention
• Vigilance increased (even at 1 mg/kg)
• Impulsiveness (probability of false alarms) reduced

The best performing quarter was at 1 mg/kg encenicline:

• selective attention reduced
• Vigilance reduced

The stop signaling paradigm (SSRT) measures the ability to stop a motor response after it has been initiated. In LHR, the SSRT was influenced by:⁸⁷

• Atomoxetine (NET reuptake inhibitor): SSRT accelerated, accuracy increased in go trials
• Citalopram (SERT reuptake inhibitor): Go response time slowed, Go accuracy reduced (at the highest dose of 1 mg/kg)
• GBR-12909 (selective DAT reuptake inhibitor): Go response time accelerated, go and stop accuracy reduced
• Guanfacine (alpha-2-adrenoceptor agonist): all important stop and go measurements worsened (at the highest dose of 0.3 mg/kg)

In LHR, a 14-day tryptophan-free diet induced locomotor activity, while no differences were seen in Wistar rats.⁸⁸

Nicotine-naive LHR do not show an increased dopamine response in the nucleus accumbens core to nicotine pretreatment, unlike Sprague-Dawley, which are not ADHD model animals.⁸⁹
Acute nicotine administration did not affect the prepulse inhibition of LHR. Chronic nicotine administration caused a marked deficit in prepulse inhibition and a significant increase in locomotor activity and [3H]nicotine binding.⁹⁰

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

3.24. IL-4 mouse¶

IL-4, given in the second week of life, increased hyperactivity and impulsivity in mice. Allergic asthma in early life had the same effect.⁹¹⁹²

3.25. Slitrk2-KO mouse¶

Slitrk2-KO mice show:⁹³

• Hyperactivity
• an altered vestibular function
• serotonergic dysregulation.

In Slitrk2-KO mice, the dopamine metabolite homovanillic acid was significantly increased in the hippocampus (+ 24 %), while no change was observed in the striatum and nucleus accumbens. There was no change in dopamine levels or its metabolites in the nucleus accumbens, where dopaminergic dysregulation can trigger hyperactivity.
Methylphenidate did not stop the hyperactivity.⁹³
Noradrenaline levels were unchanged in the various brain regions.

3.26. Roman High- (RHA) and Low-Avoidance (RLA) rats¶

The novel high-avoidance (RHA) and low-avoidance (RLA) rats are animal models for the different phenotypes of impulsivity.⁹⁴

3.27. Congenic wiggling rat (Wig rat)¶

Wig rats were developed by selecting spontaneously hyperactive specimens of Long-Evans Cinnamon (LEC) rats by gene transfer from the LEC to the Wistar King-Aptekman/Hokkaido (WKAH) strain.⁹⁵
Wig rats showed:

• Hyperactivity⁹⁶
  • Autosomal recessive inheritance⁹⁵
  • Motor activity of 12 to 14-week-old Wig rats increased significantly during the day and very significantly at night⁹⁵
  • Locomotion significantly increased in the open-field test⁹⁵
  • Straightening reduced compared to the control group⁹⁵
• Impulsiveness⁹⁶⁹⁵
• Working memory problems⁹⁶⁹⁵
• Inattention allegedly none⁶
• Y-Labyrinth test⁹⁵
  • Spontaneous switching behavior significantly impaired
  • With no change in the total number of arm entries
• Water maze test could not be carried out as the Wig rats panicked on contact with water and almost drowned⁹⁵

Congenig TIG rats continued to show:⁹⁶

• Subcutaneous injection of 4 mg/kg methamphetamine increased hyperactivity
• Low tyrosine hydroxylase levels 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, ventral striatum and 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 the sterol transporter protein 2 in all brain regions
• Increased expression of the DAT gene in the dorsal midbrain
• Reduced expression of the DAT gene in the ventral midbrain

3.28. Thyroid receptor beta mutant mouse¶

This mouse is intended to show:⁶

• Hyperactivity
• Impulsiveness
• Inattention

3.29. NK1-KO mouse¶

The NK1 receptor KO mouse should show:⁶

• Hyperactivity
• Impulsiveness
• No inattention

3.30. CdK5-dysregulated mouse¶

The CdK5-dysregulated mouse should show:⁶

• Hyperactivity
• Impulsiveness
• No inattention

3.31. Med23-KO mouse¶

Med23-KO mice showed⁹⁷

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

3.32. Ovalbumin-induced allergy mouse¶

Mice in which allergies were induced by ovalbumin:⁹⁸

• Attention impaired
  • significantly reduced visual, non-selective and non-sustained attention level
• reduced motor activity
• Social behavior impaired
  • less interest in interacting with other mice
• Communication impaired
• Increased anxiety
• Depression increased

3.33. CERS6KO mice¶

CERS6KO mice lacking CERS6 show:⁹⁹

• Hyperactivity
• Restlessness
• Nervousness
• Increased level of movement
• Increased straightening 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

3.34. CFTR-KO fish¶

Cystic fibrosis correlates with mutations in the CFTR gene¹⁰⁰, which has been identified as a gene candidate for ADHD.^101102103
CTFR-KO zebrafish show ADHD symptoms such as hyperactivity, impulsivity and attention problems.¹⁰⁴

CFTR (CNFTR) is a candidate gene for ADHD.¹⁰¹ For more information see CFTR, gene of the ciliary neurotrophic factor receptor, CNFTR In the article Monogenetic causes of ADHD.

3.35. Dogs with ADHD¶

A study of dogs with ADHD behaviors found relatively decreased blood dopamine and serotonin levels.¹⁰⁵

3.36. Drosophila (fruit fly)¶

Research on Drosophila has shown that gene variants determine the behavior of Drosophila in response to unpleasant air blasts, for example.
Drosophila that showed a particularly prolonged hyperactive reaction to bursts of air had a certain mutation in the dopamine transporter gene, which is one of the most important candidate genes for ADHD.¹⁰⁶ When these Drosophila were treated with cocaine, they calmed down more quickly.
The dopamine D1 receptor was essential for the learning behavior of Drosophila. Drosophila with an artificially silenced D1 receptor (throughout the brain) were unable to learn that a particular odor acted as a warning signal for a puff of air.¹⁰⁷
If the D1 receptor gene was repaired exclusively in the brain region of the central complex, the Drosophila were no longer hyperactive, but were still unable to learn. If, on the other hand, the D1 receptor gene was only repaired in the brain region of the “mushroom body”, the ability to learn was restored, while the hyperactivity remained.¹⁰⁶

After 60 generations, a Drosophila breeding line that was bred for sleep problems also showed considerable hyperactivity and increased sensitivity to environmental stimuli.¹⁰⁸

77 % of human disease genes have homologs in Drosophila.¹⁰⁹ Although the evolutionary tree of Drosophila and humans diverged 700 million years ago, the Drosophila brain is organized in three parts (forebrain, midbrain and hindbrain) like that of vertebrates and uses the same important neurotransmitters (dopamine, glutamate, GABA, homologues of adrenaline, noradrenaline and serotonin) as well as the corresponding enzymes, transporters and receptors.¹¹⁰¹¹¹

Drosophila under imidacloprid

Imidacloprid is a neonicotinoid that acts as an insecticide.
Imidacloprid is suspected of triggering ADHD.¹¹²

Drosophila melanogaster were exposed to an imidacloprid-containing diet for 7 days.
Their descendants showed:¹¹³

• Hyperactivity
• Aggressiveness
• changed social interaction
• repetitive movements
• Anxiety

When the offspring were exposed to a diet containing lutein nanoparticles for 24 hours, this reversed the behavioral parameters mentioned above.
Food with lutein-containing nanoparticles also protected markers of oxidative stress and cell viability and prevented the reduction of Nrf2 and Shank3 immunoreactivity.¹¹³
Lutein works

• anti-inflammatory
• antioxidant
• neuroprotective

If the mothers were fed with lutein-containing nanoparticles before fertilization, this prevented the development of imidacloprid-induced ADHD symptoms in the offspring.¹¹⁴