How do you know an animal model of a disease is really working? Researchers can create diseases such as cancer in a rat or mouse, but a tumor in a rodent may not behave the same way as a tumor in a human being. The challenge is even more difficult when scientists try to model psychiatric conditions, which in humans rely upon interviews and nuanced diagnosis. It’s hard to get a rat to stay on a therapist’s couch, much less ask whether they are feeling depressed or anxious.
So psychiatrists interested in using an animal model to probe the underlying biology of a mental condition are forced to be careful, clever and realistic. For a new model of obsessive-compulsive disorder (OCD) published last week by a team of scientists from the University of Chicago, the validity of the model was based on both the symptoms they observed in their animals and how those symptoms were treated.
More than 2 million people in the United States have been diagnosed with OCD, a condition marked by severe anxiety, repetitive behaviors, and intrusive thoughts. Yet only one drug has been found to help alleviate these symptoms – fluoxetine, a serotonin reuptake inhibitor originally developed for the treatment of depression – and the drug is only effective in roughly half of all OCD patients. Finding and testing better treatments for OCD will require animal models of the disease.
“Treatment for these people is greatly needed, and there really are very few highly valid animal models of the disorder,” said Nancy Shanahan, a postdoctoral researcher and lead author of the study in the journal Biological Psychiatry. “Having one that seems to mimic the disorder so well, especially in terms of the time course of treatments that work in humans, is potentially very useful for researching novel therapeutics.”
That’s easier said than done. The compulsive hand-washing, switch-flicking, or counting habits of human OCD sufferers would seem to be impossible symptoms to replicate in a rat, but some characteristics such as perseveration (repetitive movements or actions) and movement in an open field (a marker of a rodent’s comfort or anxiety in a strange environment) have been used by scientists as proxies for the debilitating effects of OCD. Some groups have created these behaviors by deleting genes, but for the new OCD model the UChicago team started with the unusual side effect of a migraine medication.
When the drug sumatriptan is given to people with OCD, it amplifies their symptoms, producing more intrusive thoughts and rituals. Shanahan gave her mice a similar drug that, like sumatriptan, activates a sub-class of receptors for the neurotransmitter serotonin called 1b receptors. In response, the mice showed behaviors that could be interpreted as OCD-like. Instead of exploring the entirety of their cage, they stayed close to the walls (as seen in the paths above) – a marker of high anxiety. Another test called prepulse inhibition that tests the animals’ startle response (thought to measure the brain’s ability to filter out intrusive thoughts), also revealed OCD-like behavior after the serotonin 1b drug was given.
Yet it’s still subjective to say that a mouse that paces around the walls of its cage is suffering from the same underlying biological issues as a human whose anxiety keeps them from leaving the house. More evidence was needed to prove the model’s “predictive validity” – how closely it resembles the human disease.
“A model should be evaluated on its ability to predict, not based on how much it looks like OCD,” explained Stephanie Dulawa, assistant professor in the Department of Psychiatry and Behavioral Neuroscience and senior author of the study. “The best way to do that is to evaluate manipulations with known effects in OCD.”
As a test, they pre-treated groups of animals with fluoxetine and two similar drugs with no proven effect on OCD symptoms in people. Animals were given several weeks of treatment with the drugs to mirror the slow onset of relief in humans, which can take from 4 to 8 weeks to appear. They were then given a test dose of the serotonin 1b drug, to see whether the OCD-like behaviors appeared despite their “medication.”
In the end, the mouse OCD acted like the human version. After four weeks of pre-treatment with SRIs, drug-induced OCD behaviors were reduced in the mice. Shorter SRI treatment or treatment with the other antidepressant drugs that do not work in humans with OCD were unsuccessful in reducing the behaviors caused by the drug.
“We have this time course that nicely parallels or mimics the human therapeutic response,” Shanahan said. “In order to study how these drugs are working and the pathophysiology of the disorder, we need a model where this delayed onset exists. So we are really excited about that.”
A bonus finding was found by selectively injecting the serotonin 1b drug into different regions of the brain, to try and pinpoint the neurobiological ground zero of these OCD-like behaviors. When the drug was targeted to a region called the orbitofrontal cortex, the mice showed all the same unusual behaviors they showed after a systemic injection. Injecting the drug into other areas did not produce the same results. That was more evidence that the animal model of OCD was working, the authors said.
“We found that the 1b receptors in the orbitofrontal cortex were really the critical receptors,” Dulawa said. “It was very affirming to our research because it is the brain region most heavily implicated in OCD throughout all of the human literature.”
Important as it is, creating an accurate animal model of a disease is only the first step. The ultimate goal of the laboratory is better treatments for OCD, drugs that are more effective and helpful to a larger group of patients. Blocking the serotonin 1b receptors used to create this model would be a logical first step, but no such drugs are currently available or approved, Dulawa said. Alternatively, treating OCD patients with an activator of these receptors may exacerbate symptoms initially, but have long-term benefits as the number of serotonin 1b receptors decreases from over-stimulation.
“These treatments could potentially be much more specific and work much faster,” Dulawa said. “Now that we have this model, we actually could pursue these ideas for better treatments in a disease where there is only one successful therapy.”
Shanahan, N., Velez, L., Masten, V., & Dulawa, S. (2011). Essential Role for Orbitofrontal Serotonin 1B Receptors in Obsessive-Compulsive Disorder-like Behavior and Serotonin Reuptake Inhibitor Response in Mice Biological Psychiatry DOI: 10.1016/j.biopsych.2011.07.032