Finding models for psychiatric diseases isn’t an easy feat. Inherently human in nature, psychiatric disorders are collections of different symptoms that come, go and change with age, the environement, and other unknown factors.
Modeling an inherently human psychiatric condition in animals
Given the subjective nature of many key symptoms, the lack of biomarkers and objective diagnostic tests, and the early state of the relevant neurobiology and genetics, translation of these mental states to animals is more than challenging.
“Putting all those variables into an animal model and experiment is tough. It is hard to translate the complexity of any psychiatric disorder in preclinical research,” explains Clare Stanford, Professor of Translational Neuropharmacology at UCL. “Often, preclinical scientists just look at one facet of the abnormal behavior because models do just that, model one feature of the illness”.
It is possible to experimentally induce modifications in the brain of laboratory animals or behavioural changes that are similar to those observed in humans. “But because we don’t really know what’s wrong in humans in the first place, this approach can be tricky,” adds Professor Stanford.
Modeling ADHD in animals
The conundrum is really best illustrated by attention-deficit hyperactivity disorder (ADHD). ADHD is clinically straightforward. There are only three diagnostic criteria : inattention or attention deficit, impulsivity, and hyperactivity – and all three can be measured. Despite this seemingly forthright depiction, scientists are struggling to translate the features to animal models.
“ Even diagnosing ADHD in rats and mice is amazingly difficult. You can produce evidence, but it can be difficult to be convincing. There are different types of impulsivity. There are different types of inattention. Even with something as straightforward as ADHD, it’s a very tough assignment to convince the scientific community, let alone everybody else, that the model is a pretty good model of the disorder,” explains Professsor Stanford.
Finding a hyperactive mouse
Profesor Stanford was working on depression and anti-depression drugs, looking more specifically at how amphetamine and psychostimulants – including noradrenaline – affect the brain, when she came across a hyperactive mouse.
A colony of mice arrived from Cambridge, lacking the NK1 receptor normally blocked by the drug, Sibutramine, she had been studying. The mice were supposed to behave like normal mice that have been given anti depressant. Instead, the mice were hyperactive.
Because of Professor Stanford’s background knowledge and interest in amphetamines, she decided to give them the drug to see what happened. And instead of making the mice run around, the amphetamines were doing the opposite. The mice were curling up in a corner of their cage and chilling out.
She comments : “Amphetamine doesn’t normally do that. By chance, I knew that amphetamines are used to treat ADHD. It has a calming effect in those patients. So we looked at the effect of methylphenidate, the active compound in Ritalin, which is the other drug used to treat ADHD, in the mice. And it has exactly the same effect.”
It turned out that these mice were a much better fit to model ADHD than depression.
Clare persuaded a colleague of hers, who was a pioneer in the genetics of psychiatry, to look into the mutated receptor in the mice. He had already found that a mutation in this receptor was linked to alcoholism and ADHD adults have a huge risk of alcohol abuse. Around 40% become alcoholic. Low and behold, he found strong evidence that linked the mutation in question to ADHD patients. “ I think that’s the first time, certainly one of the first times, that a discovery in mouse genetics actually predicted a finding in human beings,” explains Clare.
The importance of an ADHD mouse model
However, ADHD patients aren’t just hyperactive, they’re also impulsive and inattentive. The rest of Clare’s work helped validate this NK1– mouse as a model for ADHD.
“They turned out to be inattentive and hyperactive and impulsive and excellent – although not perfect – models for ADHD.”
The research is already pointing to different drug targets, which could help the many ADHD patients who are resistant or become tolerant to current treatments. 20% – 40% of patients with ADHD cannot achieve the treatment response and symptomatic remission. This mouse model could help find solutions for them.
Last edited: 19 October 2022 09:00
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