Investigators at the University of Wisconsin have decreased anxiety-related behaviors in monkeys with an anxious temperament by treating them with a combination of gene therapy and low doses of the atypical antipsychotic drug clozapine, which is approved for the treatment of schizophrenia and schizoaffective disorder.

Their work appeared in the December 1, 2021, print issue of Molecular Therapy after earlier publication online.

To date, brain disorders have not, by and large, profited from advances in precision medicine to the same extent that other disorders have.

The reasons for that disconnect are manifold. But one key issue is that receptors and ion channels, which make up a large fraction of the targets of neurological drugs, are not localized to specific brain areas.

Benzodiazepines, for example, target GABAergic signaling. The drugs work by quieting neuronal activity in brain regions responsible for processing emotions, especially the amygdala.

But GABA signaling is present in all areas of the brain, from the cerebral cortex to the brainstem. Fully half of inhibitory interneurons use GABA for signaling. As a result, GABAergic drugs are dangerous as well as therapeutic, and have a narrow therapeutic window. The situation is no different with other transmitter-targeting drugs.

One possible solution, becoming more clinically realistic as gene therapy hits its stride, is the use of chemogenetics. Broadly speaking, in chemogenetics researchers engineer proteins -- often receptors or ion channels -- to be responsive to small molecules they would normally ignore.

A related technology, optogenetics, makes neurons light-sensitive through the expression of light-sensitive ion channels. Optogenetics, like the older method of deep brain stimulation, requires implants, while chemogenetics can be much less invasive.

Other researchers are working on engineering further refinements into chemogenetics systems. A group at the California Institute of Technology, for example, has described a so-called ATAC (acoustically targeted chemogenetics) method that uses ultrasound waves to transiently open the blood-brain barrier in a localized manner, enabling more targeted delivery of their designer receptors.

So-called DREADDs, or designer receptors exclusively activated by designer drugs, are one form of chemogenetics. DREADDs are a system of G protein-coupled receptors (GPCRs) that have been engineered to change their response profile. Some DREADD systems use novel small molecules.

In the work now published in Molecular Therapy, the team used clozapine, because it is an approved therapeutic that has been successfully used in DREADD systems.

The team first administered the clozapine-sensitive designer receptors to the amygdala of monkeys with an anxious temperament. The animals were then treated with clozapine to see whether the DREADD system affected their response to an anxiety-generating stimulus in form of exposure to a stranger.

The team found that animals treated with low doses of clozapine showed less anxious behavior in the presence of a stranger if they were expressing designer receptors in the amygdala. In animals without the designer receptors, those low doses did not have an effect on behavior, although the researchers did note that clozapine lowered levels of the stress hormones cortisol and adrenocorticotropic hormone (ACTH).

The authors wrote that their work has further preclinical as well as clinical implications. For one thing, "In future studies, chemogenetic technology could be similarly applied to functionally define the role of other cortical and subcortical components of the neural circuitry underlying primate anxiety," they wrote. And "demonstrating the ability to manipulate neural circuits using chemogenetic methods to reduce [nonhuman primate] anxiety is an important step toward developing novel treatments for refractory psychiatric illnesses, including severe human anxiety disorders."

In an accompanying editorial, researchers from the Mount Sinai School of Medicine and Oregon Health & Science University agreed, writing that "the challenges of choosing appropriate [DREADD] actuator drugs and viral vector systems are substantial but not insurmountable."