Animal models that do not adequately represent ADHD

In addition to the animal models described in previous articles, which exhibit many ADHD symptoms, there are several other animal models that exhibit only some ADHD symptoms or are unsuitable for describing the etiology of ADHD for other reasons:¹²

4.1. Dopamine heteroreceptor knockout mice¶

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

There are mouse models that lack DRD1, DRD2, DRD3, DRD4, or DRD5. Most of them do not exhibit ADHD symptoms.
The DRD4-KO mouse has been studied most frequently.

4.1.1. DRD4 knockout mice¶

D4R-KO mice lack the dopamine D4 receptor.

D4R-KO mice show

• Hyperexcitability of frontal cortical P-neurons³⁴
• In contrast, the gain-of-function of the D4 receptor caused by the D4.7R gene variant results in a decrease in corticostriatal glutamatergic transmission⁵
• No hyperactivity
  • Motor activity increases only during the first 5 minutes in a new environment⁶
• No increased impulsivity⁶
  • Neither impulsivity in action nor impulsivity in choice
• No increased novelty seeking⁶
• Inattention
  • According to some accounts, it has not increased
  • Attention Deficit in a 5-Choice Continuous Performance Test (5C-CPT)
• Increased sensitivity:⁷
  • Alcohol
  • Cocaine
  • Methamphetamine

Dopamine release in the dorsal striatum is reduced.⁸
Dopamine synthesis and the conversion of dopamine to the metabolite DOPAC are increased.⁸
The results suggest that D4 receptors influence presynaptic dopamine levels.

4.1.2. DRD2 knockout mice¶

Develop D2R knockout mice

• Characteristics of Parkinson’s disease⁹
• Prolactinomas¹⁰
• chronic pituitary hyperplasia¹⁰¹¹
• a moderate decrease in MSH levels¹⁰¹¹
• D2L-/- mice (with presynaptic D2S autoreceptors that are still functional) showed¹²
• reduced mobility
• reduced tendency to wind up
• significantly less catalepsy and inhibition of motor activity caused by haloperidol
• initial suppression of motor activity by quinpirol, similar to that observed in the wild type
• The D2S receptor functioned as an impulse-modulating autoreceptor in the mutant mice roughly as well as D2L.

4.2. WKHA Council¶

• Hyperactive
• Not impulsive
• No problems with sustained attention

The WKHA-Ratten does not appear to be representative of ADHD.¹²

4.3. A callosal mouse¶

• Hyperactivity
  • Only becomes hyperactive with age
• Impulsive
  • Impulsivity decreases as the number of tests increases; this is not consistent with ADHD
• Impairment in conditioned learning tasks

The Akallosale Mouse is not representative of ADHD.²¹

4.4. Hyposexual advice¶

The hyposexual rat does not appear to be a suitable model for ADHD.²¹

4.5. PCB-exposed rat¶

• Hyperactivity
• No problems with sustained attention

Rats exposed to PCBs do not develop ADHD.¹²

4.6. Lead-exposed mouse¶

• Hyperactivity
• Ataxia
• Other symptoms of lead poisoning can be easily distinguished from ADHD

The lead-exposed mouse does not adequately represent ADHD.²¹

4.7. Rat raised in social isolation¶

• Hyperactivity in a New Environment
• Increased omission errors
• Endurance issues
• No impulsivity
• No impairment in task detection as measured by the 5-choice serial reaction time (5-CSRT) test for sustained attention

As a result, rats raised in social isolation do not fully exhibit ADHD.¹²

4.8. TAAR-1-KO mouse¶

• Reduced prepulse inhibition¹³
• Unchanged:¹³
  • Weight, Height, Body Temperature
  • Anxiety-related behavior
  • Stress Responses
• Amphetamine use¹³
  • Has a stronger psychomotor stimulating effect
  • Increased levels of dopamine and norepinephrine 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 striatum compared to 18.5% in normal mice)

4.9. MACROD1- and MACROD2-knockout mice¶

MACROD1-KO mice show:

• Motor coordination problems¹⁴
  • Only in females

MACROD2-KO mice show:

• Hyperactivity¹⁴
  • To continue increasing with age
• Bradykinetic gait (slower, shuffling gait, as seen in Parkinson’s disease)

4.10. Neonatal Nicotine Mouse¶

Rats that were exposed to nicotine before birth or during the first few days of life showed

• Hypoactivity following nicotine exposure on days 8 through 14¹⁵

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

• Hyperactivity¹⁶
  • in both male and female offspring
  • Peak during the “active” or dark phase of the light-dark cycle
  • reduced by oral MPH
  • otherwise: no spontaneous hyperactivity¹⁷
• Attention problems¹⁷
  • only in males
• Working memory problems¹⁷
  • only in males
• no impulsivity¹⁷
• no anxiety-like behavior¹⁷

4.11. 5-HT2C knockout mouse¶

The serotonin 2c receptor knockout mouse showed:¹⁸

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

4.12. 5-HT1B knockout mouse¶

The serotonin 1b receptor knockout mouse showed:

• Impulsivity¹⁹
  • Increased impulsivity in behavior
  • Unchanged impulsivity in decision-making
• Hyperactivity in both young and adult animals²⁰
• Reduced anxiety²⁰
• Increased Aggression²¹²²
• No hyperlocomotor response to the 5-HT1A/1B agonist RU24969²¹²²
• No prepulse inhibition by the 5-HT1A/1B agonist RU24969²³

Chronic—but not subchronic—treatment with fluoxetine and a 5-HTT knockout significantly attenuate the PPI deficits and perseverative hyperlocomotion induced by 5-HT1B agonists.²⁴

4.12. NAchR-KO mice¶

Nicotine-acetylcholine receptor knockout mice exhibited different symptoms depending on the receptor subtype that was inactivated:

• Alpha 5: Decrease in accuracy²⁵
• Alpha 7: Attention Deficit in the 5CSRTT²⁶
• Beta 2: Deficit in sustained attention (5CSRTT)²⁷

4.13. GFAP-DNSynCAM1 Mouse¶

The adhesion molecule SynCAM1 is involved in the differentiation and organization of synapses.
In astrocytes²⁸

• Does SynCAM1 mediate adhesive communication?
  • between astrocytes
  • between glial cells and neurons
• SynCAM1 is functionally linked to erbB4 receptors, which are involved in regulating both neuronal and glial development as well as mature neuronal and glial function

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

• disrupted daily physical activity
  • increased and more frequent episodes of activity during the day (when the animals normally sleep)
  • shorter rest periods
• high baseline activity in the dark (during the rodents’ waking/active period)
  • AMP reduces these
• Reduces anxiety
  • avoidable and unavoidable stimuli

4.14. 14-3-3γ Heterozygous knockout mice¶

While monozygotic 14-3-3γ KO mice die before birth, heterozygous 14-3-3γ KO mice show:²⁹

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

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

• Williams-Beuren syndrome (Williams syndrome)
• Creutzfeldt-Jakob disease

4.15. NMDA agonist mouse¶

MK-801 (dizocilpin) is an N-methyl-D-aspartate receptor agonist that can induce various symptoms of different neuropsychiatric disorders in a dose-dependent manner. In mice, it causes:³⁰
Low-dose MK-801 (0.01 mg/kg):

• Impaired spatial memory
• Impulsivity
  Moderate dose of MK-801 (0.12 mg/kg):
• Hyperactivity
• social deficits
  High-dose MK-801 (0.2 to 0.3 mg/kg):
• poor personal hygiene

4.16. HNMT-KO mouse¶

HNMT breaks down histamine. HNMT-KO mice have histamine levels in the brain that are five times higher than normal. Although elevated histamine levels in the brain are suspected to contribute to ADHD, HNMT-KO mice exhibit only a few typical ADHD symptoms:³¹

• Increased aggression
  • Serotonin levels unchanged
  • The H2R antagonist zolantidine reduced aggression
  • The H1R antagonist pyrilamine did not alter aggression
• Sleep phases shifted, circadian rhythm disrupted
  • increased alertness during hours 0 to 6 (inactive period, darkness)
  • reduced alertness during the day between 12 and 18 (active period, daylight)
  • Average duration of waking periods during the day increased from 0 to 6
  • Total number of wake and sleep phases remains unchanged
  • EEG activity
    • elevated in the range of 3.0–5.5 Hz while awake
    • During non-REM sleep
      • EEG activity of slow waves (0.5–4.0 Hz) remains unchanged
      • Reduced EEG theta activity (5.0–10.0 Hz) during both the light and dark periods
    • remains unchanged during REM sleep
  • The H1R antagonist pyrilamine reversed the reduced alertness in bright light but left the increased alertness in the dark unchanged
  • The H2R antagonist zolantidine did not affect alertness
  • The reduced alertness during the dark period appears to be a compensatory response to the prolonged alertness during the light period
• Reduced physical activity in the field test
  • Length of stay in the central area remains unchanged
• unchanged:
  • Anxiety-related behavior
  • Motor skills
    • motor control
    • motor activity
  • Working memory
  • passive avoidance
  • Learning/Memory
  • Sensitivity to pain
  • social interaction

4.17. BTBR T+ Itpr3tf/J Mouse: ADHD and ASD (AuDHS) Model¶

The BTBR T+ Itpr3tf/J mutant mouse (BTBR) could serve as a model for AuDHS (ADHD and ASD comorbidity).³²
BTBR mice (Black and Tan BRachyury T+Itpr3tf/J) exhibit³³

• Symptoms of AS
  • Impaired sociability
  • altered ultrasonic vocalization
  • increased self-care behaviors
• ADHD symptoms
  • cognitive
  • emotional
• Intranasal dopamine administration corrected the deficits
  • non-selective attention
  • object-oriented attention
  • social integration
• dopaminergic changes
  • lower striatal DAT
  • reduced D2R-mediated neurotransmission
  • unchanged D1 receptor-mediated neurotransmission
  • reduced tyrosine hydroxylase expression in
    • Substantia nigra
    • VTA
    • dorsal striatum
  • Increased spatial coupling between vesicular glutamate transporter 1 (VGLUT1) and TH signals
  • unaffected GABAergic neurons

When exposed to high doses of various stimulants, BTBR mice did not exhibit behavioral stereotypes but rather a dramatic increase in motor activity. In contrast, the C57 mice used as controls developed the motor stereotypes that would typically be expected.³²

• The PPARα agonist PEA improved autistic symptoms (repetitive and stereotypical behaviors as well as social skills) in BTBR mice³⁴ as well as in a VPA-induced ASD mouse model.³⁵
• The H3R, D2R, and D3R antagonist ST-713 improved autistic-like behavior in male BTBR T+tf/J mice:³⁶
  • social deficits
  • repetitive/compulsive behaviors
  • anxiety disorders
  • but not the hyperactivity of the tested mice
  • 5 mg i.P. reduced the elevated protein levels in the hippocampus and cerebellum of
    • NF-κB p65
    • COX-2
    • iNOS
  • Concomitant administration of an HR agonist or an anticholinergic agent reversed the improvement in social parameters
• The H3R/D2R/D3R receptor antagonist ST-2223, at doses of 2.5, 5, and 10 mg/kg, administered intraperitoneally (i.p.), significantly and dose-dependently alleviated social deficits and anxiety-like behaviors in BTBR mice. In addition, it caused³⁷³⁸
  • Increase in histamine in
    • Cerebellum
    • Striatum
  • Increase in dopamine in
    • PFC
    • Striatum
  • Increase in acetylcholine in
    • PFC
    • Striatum
    • Hippocampus

4.18. Mice Used as Physical Trauma Models¶

Mice with physical trauma models may exhibit symptoms similar to those of ADHD.
These models are based on the direct effects of physically induced stress or trauma on an animal, e.g.:³⁹

• X-rays
• neonatal hypoxia
• Cerebellar growth disorders, etc.

Conceptually, these are models of secondary ADHD.