DREADDs Could Guide More Targeted Treatments in Future

An innovative experimental technique called DREADDs—Designer Receptors Exclusively Activated by Designer Drugs—which uses surgically implanted manmade receptors to modify brain function, may someday provide a therapy for treatment of severe refractory psychiatric disorders.

Animal studies have shown that DREADDs can be surgically delivered to a population of brain cells thought to be compromised in patients with psychiatric disorders. Once in place, the receptors can be activated or inactivated through an injection of a specific drug.

The hope is that by implanting and manipulating DREADDs in a precisely targeted brain region associated with a neuropsychiatric disorder, therapeutic benefits could be provided absent the unwanted side effects associated with drugs.

So far DREADDs have been studied only in rodents and nonhuman primates. But clinical application is the next frontier, according to Mike Michaelides, Ph.D., chief of the Biobehavioral Imaging and Molecular Neuropsychopharmacology Unit at the National Institute on Drug Abuse (NIDA).

“Given the absence of any significant psychopharmacological breakthroughs in recent years, there is a palpable hunger for better ways to treat mental disorders,” he said.

Among those who see real-world clinical application on the horizon is psychiatrist Ned Kalin, M.D., chair of the Department of Psychiatry at the University of Wisconsin-Madison School of Medicine and Public Health. There he runs a laboratory, which combines molecular, preclinical animal models, and human functional imaging studies to understand the neurobiology underlying anxiety and mood disorders. Kalin’s lab is now working with rhesus monkeys and has shown that DREADDs can be safely applied and that the implanted receptors will function within the neural circuits of these animals.

The next step, said Kalin, is testing DREADDS in monkeys who demonstrate anxiety-like behaviors, something he anticipates could take place within the next two years.

Anxiety is a good initial neuropsychiatric target because the neural circuitry of anxiety is better understood than for other psychiatric disorders, he noted. “There is every indication to believe that this is going to work, so it’s not whether we’re going to get there, but when are we going to get there,” he added.

In 2016, psychologist and neuroscientist David Amaral, Ph.D., of the University of California, Davis, published an article demonstrating use of DREADD technology to modify activity in the rhesus amygdala—a brain region known to play a role in emotional learning in the context of fear and anxiety. That research, however, was exploratory and not directed specifically at modeling anxiety treatment. In rodents, however, DREADDs have pointed to the role of specific cells involved in anxiety-like behaviors, drug and alcohol seeking, and symptoms of Parkinson’s disease.

Even as studies involving DREADDs in animal models advance, questions remain about their translational potential. One of these questions involves whether DREADDs may have unintended effects on off-target populations of brain cells. In a 2016 article in the Journal of Neuroscience, scientists reported that DREADDs implanted in rodents altered neuronal activity even in the absence of an activating drug.

Given that DREADD implantation involves invasive intracranial neurosurgery, there will also be hurdles getting FDA approval, Kalin noted.

While Kalin said he currently sees no alternative to intracranial delivery of the DREADDs, he noted the FDA has approved invasive techniques in the past, including deep brain stimulation for Parkinson’s disease. The delivery of DREADDs is key to the technology’s therapeutic potential because it allows precise placement, he observed. “You can then have a very targeted circuit-based therapy that would allow you to get around all the problems with medications” that occur because they impact targets unrelated to the disorder.

In animal studies, scientists have used radioactive tracers to observe how DREADDs react when the appropriate activating drug is administered. The process uses positron emission tomography (PET), a technology long used in neuroimaging research. The radioactively tagged molecules show up as lighter and darker areas as the DREADD is turned up or down during drug administration, NIDA’s Michaelides explained.

In future clinical applications, this would allow real-time monitoring of response in brain circuits. Clinicians would then have a way to fine-tune how much of the activating drug is administered based on individual response. In animal research scientists have used PET to observe the correlation between DREADD activation and behavioral changes, and the hope is that this same utility will be found in eventual clinical application, Michaelides said. ■

Amaral’s study, “The Rhesus Monkey Connectome Predicts Disrupted Functional Net-works Resulting From Pharmacogenetic Inactivation of the Amygdala” can be accessed here. “DREADDs: Use and Application in Behavioral Neuroscience” is available here.