McLean investigator is optimizing animal models to accelerate neuropsychiatric drug development in humans
Brian Kangas, PhD, is on a decadelong mission to show how complex behavior in laboratory animals has a considerable role in advancing human neuropsychiatric medications for conditions like addiction, PTSD, chronic stress and depression.
As the Director of the Cognition Biology Laboratory at McLean Hospital, Kangas started this quest by designing and building animal test apparatus-–a touchscreen-based device—and then observing how rodents and non-human primates respond in a series of cognitive tests involving the device. The testing is significant in ultimately determining how candidate medications in the pipeline at various pharmaceutical companies will be put into successful practice by human patients.
Kangas’ primary focus lies in how complex animal behavior can inform drug development. He is evaluating both the desirable effects of candidate medications as well as their potential unwanted side effects on various aspects of animal cognition. This work, he believes, can serve as important preclinical predictors of a new drug’s efficacy and safety profile in human use.
In addition, he’s also studying the effects of abused drugs on cognition to learn how drugs like marijuana, cocaine, and the prescription opioids affect learning, memory, vigilance, and other cognition-related behaviors. Both initiatives are somewhat linked.
Studying drugs of abuse and candidate medications, for instance, can often have a reciprocal way of informing each other. That is because existing drugs, while effective in treating disease, can have adverse side effects. Opioids manage pain quite well but are associated with addiction. Cannabis products help with nausea and appetite stimulation, both helpful for chemotherapy patients, but chronic use can lead to unwanted deficits in learning and memory. By designing studies that examine the existing drug as a standard allows the Kangas team to engage in rigorous appraisals of new candidate therapeutics to accelerate development of medications.
The most recent and exciting approach in the Kangas lab prioritizes reverse translational methods, that is, computerized tasks initially developed for use in human participants and subsequently modified by Kangas and colleagues for testing in lab animals. This is well-suited for the touchscreen device and has been especially productive in evaluating medications designed for treatment-resistant depression.
Major depression is often associated with a loss of pleasure in previously rewarding activities, or anhedonia, and this symptom is often resistant to frontline antidepressants, such as SSRIs (selective serotonin reuptake inhibitors). One of the factors in being able to develop effective drugs to treat depression centers on reward learning, the sensitivity to positive reinforcement during task performance, which is similar in both human participants and laboratory rats. In healthy individuals and rodents, reward learning responses are biased in favor of so-called “rich” rewards, as opposed to those that are “lean.” But that’s not so in humans with depression and rodents exposed to chronic stress.
Participants with depression typically exhibit lower response biases for richly rewarded stimuli, and this blunting correlates with self-reported anhedonia. In order to accelerate drug development for mood disorders, like depression, quantitative approaches are needed to objectively measure reward learning as a means to identify deficits. This then can serve as a behavioral biomarker in developing medications to counter anhedonia in neuropsychiatric disorders.
How Kangas’ animal testing works: The touchscreen device resembles a small chamber about the size of a kitchen microwave; it includes software which was also designed in-house. The animal test-takers learn a reward is imminent once a certain behavior is exhibited. Contingencies, some more richly rewarded than others, are introduced, which produce response biases. The effects of drugs designed to produce antidepressant-like effects are then evaluated for their ability to enhance adaptive reward learning. And, indeed, drugs already shown to produce pro-hedonic effects in humans, like ketamine, amphetamines and MDMA, readily increase reward learning under laboratory conditions arranged.
Conclusion: Modern touch-sensitive technology provides a flexible means to expose an experimental subject to a variety of complex behavioral tasks designed to test dimensions of cognitive function before, during, and after drug administration. In turn, these assessments can inform the safety and efficacy of newly designed pharmacotherapeutics for anhedonia and beyond.
“Brian has dedicated his research efforts to the exploration of anhedonia, and he has pioneered the development of a method facilitating the assessment of anhedonia in a rodent model, drawing inspiration from established human testing processes,” says Sherene Shenouda, PhD, Director, Business Development and Licensing. “This innovative testing approach has positioned Brian to collaborate with industry partners in evaluating proprietary compounds with potential applications for treating this condition.”
Supported by the National Institute on Drug Abuse, National Institute of Mental Health, Department of Defense, NASA and the biopharmaceutical industry, Kangas’ research has had influence on informing the development of more than 20 drugs within the last four years.
“Brian's fervent dedication to his work underscores his commitment to advancing the understanding and treatment of anhedonia, with the potential to significantly impact the lives of millions worldwide who suffer from this condition,” said Shenouda.