June 22, 2021

About 30 percent of people who have severe anxiety and depression do not find sufficient relief in available medications and psychotherapy, causing them chronic, debilitating symptoms and a significant risk of suicide. To help end this debilitation, University of Wisconsin–Madison researcher Ned Kalin, MD, and his team are studying how to dial down overactive responses to potential threats.

The researchers are using an established method, called DREADDs (Designer Receptors Exclusively Activated by Designer Drugs), in monkeys at the Wisconsin National Primate Research Center (WiNPRC) to make small changes to genes in targeted cells to alter cell behavior. The idea is to coax neurons to produce a unique version of a protein, called a receptor. These “designer receptors” can receive chemical signals that regulate the cells’ function and affect how they communicate with other cells. Unlike other receptors in the brain that respond to naturally occurring chemical signals, the DREADDs only respond to a chemical not naturally present — a “designer” drug matched to the designer receptor.

“When such a drug interacts with DREADDs, you have the possibility of ‘fine-tuning’ the function of the brain cell that is now expressing this receptor,” says Patrick Roseboom, PhD, senior scientist and a lead study author.

The researchers injected a low dose of a psychiatric medication, Clozapine, in five monkeys to activate DREADDs in cells in the amygdala, the brain region responsible for regulating emotions. The researchers then tested the monkeys in a mildly stressful situation, placing them near an unfamiliar human, which is similar to how healthcare professionals assess anxiety levels in children. The researchers’ observations of the monkeys’ behavior and levels of stress hormones showed the most anxious monkeys freeze — becoming quiet and very still.

When the researchers gave the Clozapine before the stressful situation, the monkeys with the DREADDs experienced a significant reduction in freezing, while a control group without the DREADDS showed no change in behavior. 

The success of this proof-of-concept study is providing hope for using gene therapy and methods, such as DREADDs, to treat the millions of people who live with severe and treatment-resistant psychiatric illnesses. Read more about the NPRCs’ anxiety and depression research here.


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