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ADHD in animal models


ADHD in animal models

Rodents are very popular as animal models because they are very similar to humans, are easy to keep and their development cycles and metabolism are much faster. One day in the life of a rat is equivalent to about 27 days in a human.1 However, due to the accelerated metabolism, the required dose of stimulants is also increased, so that rats require almost twice as high doses of MPH as humans, which must be taken into account when assessing drug studies.

There are various rat breeds that represent ADHD-HI, ADHD-I and non-affected individuals as animal models. They are used to investigate which neurophysiological changes are associated with which symptoms. There are two groups of model animals: those that have been bred or selected for specific symptoms and those in which a singular change has been induced (usually a single gene is deactivated (e.g. DAT-KO) or a single neurotransmitter (e.g. dopamine) is eliminated).

In the first group, the Spontaneous(ly) Hypertensive Rat (SHR) represents a form of ADHD-HI (with hyperactivity), while Wistar-Kyoto rats (WKY) usually represent non-affected individuals. In addition, the SHR/NCrl is an SHR strain that shows symptoms of ADHD-C and the WKY/NCrl is a strain that shows symptoms of ADHD-I (attention deficit without hyperactivity).2345 If studies do not differentiate this, it can generally be assumed that the Wistar-Kyoto rats (WKY) refer to the non-affected model.
The fact that these animal models develop their symptoms solely due to their genetic make-up and without the influence of early childhood stress,6 shows that certain gene variants alone can also represent a separate pathway for the development of mental disorders such as ADHD and that the two pathways of genes alone and genes + environment exist side by side.
Interestingly, SHRs already have a disturbed HPA axis (stress axis) due to their genetic predisposition alone.

In rodents, the predominant glucocorticoid is corticosterone, rather than cortisol, which is predominant in humans. Otherwise, the stress systems of rodents and hominids are surprisingly similar, despite the 90 million years or so that separated their evolutionary lineage.
ADHD is also discussed in dogs.7 An ADHD rating scale for dogs showed reliable results8

The various animal models clearly show that symptoms such as hyperactivity, impulsivity or attention problems can be triggered by very different causes. The mediation of symptoms must be distinguished from the causes (e.g. a specific genetic defect). For example, very different causes (e.g. genetic defects) can lead to a dopamine deficit or others to a dopamine surplus, both of which in turn cause almost identical symptoms due to the deviation from the optimal dopamine level (inverted-U).9 To illustrate this, we have divided the animal models, as far as we know, into those with a dopamine deficiency and those with a dopamine excess. Although dopamine is the most important factor in ADHD, the other influences also contribute.
Whether a hypo- or hyperdopaminergic state prevails extracellularly is of little relevance in our understanding - both are associated with ADHD symptoms. Extracellular dopamine levels are too low in overactive DAT, and the phasically released dopamine is already reabsorbed by overactive DAT before it can transmit its signal to the receptors. In underactive DAT, extracellular dopamine levels are too high, so that it interferes with signal transmission as noise. Most importantly, there is a lack of reuptaken dopamine to replenish the vesicles for phasic dopamine release.
Both extracellular hyperdopaminergic and hypodopaminergic states impair signal transmission through phasic dopamine.

The most commonly used criteria for model validity include face validity, construct validity and predictive validity.
Apparent validity: Reliability with which the model reproduces certain state characteristics (e.g. the behavioral symptoms of a psychiatric disorder).
Construct validity: reliability with which the model measures what it is supposed to measure (etiology and pathogenesis of a disorder)
Predictive validity (predictive validity): Reliability with which the model predicts the relationship between a triggering factor and an observable effect of the disease on the one hand and the observable effects of a therapeutic agent on the disease on the other.

Interestingly, mouse models in which the dopamine receptors were deactivated show hardly any ADHD symptoms, which further emphasizes the importance of DAT and its influence on extracellular and phasic dopamine.

We subdivided the animal models according to extracellular dopamine levels:

1. ADHD animal models with reduced extracellular dopamine
2. ADHD animal models with increased extracellular dopamine
3. ADHD animal models with (to us) unknown dopamine changes
4. Animal models that inadequately represent ADHD

  1. Agoston DV (2017): How to Translate Time? The Temporal Aspect of Human and Rodent Biology. Front Neurol. 2017 Mar 17;8:92. doi: 10.3389/fneur.2017.00092. PMID: 28367138; PMCID: PMC5355425.

  2. Sagvolden, Dasbanerjee, Zhang-James, Middleton, Faraone (2008): Behavioral and genetic evidence for a novel animal model of Attention-Deficit/Hyperactivity Disorder Predominantly Inattentive Subtype. Behav Brain Funct. 2008 Dec 1;4:56. doi: 10.1186/1744-9081-4-56. PMID: 19046438; PMCID: PMC2628673.

  3. 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.

  4. 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.

  5. 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.

  6. Spontaneously Hypertensive (SHR) Rats: Guidelines for Breeding, Care, and Use; National Academies, 1976 – 20 Seiten

  7. Bleuer-Elsner, Zamansky, Fux, Kaplun, Romanov, Sinitca, Masson, van der Linden (2019): Computational Analysis of Movement Patterns of Dogs with ADHD-Like Behavior. Animals (Basel). 2019 Dec 13;9(12). pii: E1140. doi: 10.3390/ani9121140.

  8. Csibra B, Bunford N, Gácsi M (2024): Development of a human-analogue, 3-symptom domain Dog ADHD and Functionality Rating Scale (DAFRS). Sci Rep. 2024 Jan 20;14(1):1808. doi: 10.1038/s41598-024-51924-9. PMID: 38245569; PMCID: PMC10799898.

  9. Cools R, D’Esposito M (2011): Inverted-U-shaped dopamine actions on human working memory and cognitive control. Biol Psychiatry. 2011 Jun 15;69(12):e113-25. doi: 10.1016/j.biopsych.2011.03.028. PMID: 21531388; PMCID: PMC3111448. REVIEW