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Animal models that inadequately represent ADHD

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Animal models that inadequately represent ADHD

4. Animal models that inadequately represent ADHD

In addition to the animal models presented in the previous articles, which show many ADHD symptoms, there are several other animal models that only show some symptoms of ADHD or are not suitable for describing the etiology of ADHD for other reasons:12

4.1. Dopamine heteroreceptor KO mice

Heteroreceptors are receptors that sit on neurons of other neurotransmitters. In contrast, autoreceptors sit on the neurons of their own neurotransmitter (e.g. D2 autoreceptors, which sit on dopamine neurons and (auto)regulate them).
For the D2 autoreceptor KO mouse, see above.

There are mouse models that lack DRD1, DRD2, DRD3, DRD4 or DRD5. Most of them do not show ADHD symptoms.
The DRD4-KO mouse was examined most frequently.

4.1.1. DRD4-KO mice

D4R-KO mice do not have a dopamine D4 receptor.

Show D4R-KO mice

  • Hyperexcitability of frontal cortical P neurons34
  • The gain of function of the D4 receptor by the D4.7R gene variant, on the other hand, shows a decrease in cortico-striatal glutamatergic transmission5
  • No hyperactivity
    • Motor activity only increased in the first 5 minutes in a new environment6
  • No increased impulsivity6
    • Neither action impulsivity nor choice impulsivity
  • No increased novelty seeking6
  • Inattention
    • Not increased according to some accounts
    • Attention deficit in a 5-choice continuous performance test (5C-CPT)
  • Increased sensitivity to7
    • Alcohol
    • Cocaine
    • Methamphetamine

Dopamine release in the dorsal striatum is reduced.8
Dopamine synthesis and dopamine conversion to metabolite DOPAC increased.8
The results indicate an influence on presynaptic dopamine levels through D4 receptors.

4.1.2. DRD2-KO mice

Developing D2R knockout mice

  • Characteristics of Parkinson’s disease9
  • Prolactinomas10
  • chronic pituitary hyperplasia1011
  • a moderate decrease in the MSH content1011
  • D2L-/- mice (with still functional presynaptic D2S autoreceptors) showed12
  • reduced locomotion
  • reduced winding behavior
  • significantly less catalepsy and inhibition of locomotor activity due to haloperidol
  • initial suppression of motor activity by quinpirole similar to wild type
  • D2S receptor functioned in the mutant mice about as well as D2L as a pulse-modulating autoreceptor.

4.2. WKHA advice

  • Hyperactive
  • Not impulsive
  • No problems with sustained attention

4.3. Acallosal mouse

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

4.4. Hyposexual advice

4.5. PCB-exposed rat

  • Hyperactivity
  • No permanent attention problems

4.6. Lead-exposed mouse

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

4.7. Rat reared in social isolation

  • Hyperactivity in a new environment
  • Increased omission errors
  • Stamina problems
  • No impulsiveness
  • No impairment in the measurement of task acquisition in the 5-choice serial reaction time (5-CSRT) test for sustained attention

4.8. TAAR-1-KO mouse

  • Reduced prepulse inhibition13
  • Unchanged:13
    • Weight, height, body temperature
    • Anxiety behavior
    • Stress reactions
  • Amphetamine administration13
    • Has a stronger psychomotor stimulating effect
    • Increased increase in dopamine and noradrenaline in the dorsal striatum
    • Correlates with a 262 % increase in high-affinity D2 receptors (D2-high) in the striatum (48.5 % D2-high receptors in the stratum compared to 18.5 % in normal mice)

4.9. MACROD1 and MACROD2-KO mice

MACROD1-KO mice show:

  • Motor coordination problems14
    • Only for females

MACROD2-KO mice show:

  • Hyperactivity14
    • Increasing with age
  • Bradykinetic gait (slower and shuffling gait, as in Parkinson’s disease)

4.10. Neonatal nicotine mouse

Rats that were exposed to nicotine prenatally or in the first days of life showed

  • Hypoactivity with nicotine exposure on day 8 to 1415

Rats whose mothers were exposed to nicotine during pregnancy and during the first weeks after giving birth showed

  • Hyperactivity16
    • in both male and female offspring
    • Climax during the “active” or dark phase of the light-dark cycle
    • reduced by orally administered MPH
    • different: no spontaneous hyperactivity17
  • Attention problems17
    • only for males
  • Working memory problems17
    • only for males
  • no impulsiveness17
  • no anxiety-like behavior17

4.11. 5-HT2C-KO mouse

The serotonin 2c receptor KO mouse showed:18

  • Attention problems in the 5-choice serial reaction time task (5CSRTT)
  • Learning problems
  • no inhibition problems

4.12. NAchR-KO mice

Nicotinic acetylcholine receptor KO mice showed different symptoms depending on the receptor subtype deactivated:

  • Alpha 5: Decrease in accuracy19
  • Alpha 7: Attention deficit with 5CSRTT20
  • Beta 2: Deficit in sustained attention (5CSRTT)21

4.13. GFAP-DNSynCAM1 mouse

The adhesion molecule SynCAM1 is involved in the differentiation and organization of synapses.
In astrocytes22

  • synCAM1 mediates adhesive communication
    • between astrocytes
    • between glia and neurons
  • synCAM1 is functionally linked to erbB4 receptors, which are involved in the control of both neuronal/glial development and mature neuronal and glial function

Mice with an astrocyte-specific dominant-negative form of SynCAM1 (GFAP-DNSynCAM1 mice) show

  • movement activity disturbed during the day
    • increased and more frequent episodes of activity during the day (when the animals normally sleep)
    • shortened rest periods
  • high basic activity in the dark (the rodents’ waking/active time)
    • AMP reduces these
  • Anxiety reduced
    • to avoidable and unavoidable stimuli

4.14. 14-3-3γ-Heterozygous KO mice

While monozygous 14-3-3γ KO mice die before birth, heterozygous 14-3-3γ KO mice exhibit:23

  • Developmental delay
  • Hyperactivity
  • Depression-like behavior
  • increased sensitivity to acute stress

14-3-3γ plays a diverse role in cellular processes. 14-3-3γ is enriched in the brain.
14-3-3γ is involved in neurological and psychiatric diseases, e.g.

  • Williams-Beuren syndrome
  • Creutzfeldt-Jakob disease

4.15. NMDA agonist mouse

MK-801 (dizocilpine) is an N-methyl-D-aspartate receptor agonist that can induce various symptoms of different neuropsychiatric disorders in a dose-dependent manner. Newirkt in mice:24
Low-dose MK-801 (0.01 mg / kg):

  • Spatial memory impaired
  • Impulsiveness
    Medium dose MK-801 (0.12 mg / kg):
  • Hyperactivity
  • social deficits
    High-dose MK-801 (0.2 to 0.3 mg / kg):
  • reduced self-hygiene

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  13. Wolinsky, Swanson, Smith, Zhong, Borowsky, Seeman, Branchek, Gerald (2007): The Trace Amine 1 receptor knockout mouse: an animal model with relevance to schizophrenia. Genes Brain Behav. 2007 Oct;6(7):628-39. doi: 10.1111/j.1601-183X.2006.00292.x. PMID: 17212650.

  14. Crawford, Oliver, Agnew, Hunn, Ahel (2021): Behavioural Characterisation of Macrod1 and Macrod2 Knockout Mice. Cells. 2021 Feb 10;10(2):368. doi: 10.3390/cells10020368. PMID: 33578760; PMCID: PMC7916507.

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  23. Kim DE, Cho CH, Sim KM, Kwon O, Hwang EM, Kim HW, Park JY. 14-3-3γ Haploinsufficient Mice Display Hyperactive and Stress-sensitive Behaviors. Exp Neurobiol. 2019 Feb;28(1):43-53. doi: 10.5607/en.2019.28.1.43. PMID: 30853823; PMCID: PMC6401549.

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