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Researchers develop a selective chemogenetic actuator to rapidly control neuronal activity and behavior

Chemogenetics is a fairly new area of neuroscience that explores the use of synthetically derived receptors and selective ligands to temporarily activate or deactivate specific brain areas. These receptors are also known as DREADDs (Designer Receptors Exclusively Activated by Designer Drugs). DREADDs are now widely used in neuroscience and biology to modify neural activity and behavior temporarily.

So far, the chemogenetic actuator that was most commonly used in DREADD implementations is clozapine-N-oxide (CNO). While it has sometimes proved valuable in neuroscience studies, this actuator has a number of drawbacks and limitations, including a slow action and possible side effects associated with its back-metabolism into clozapine, a different actuator that has been found to have extensive off-target effects.

With this in mind, researchers at the National Institute of Radiological Sciences in Japan and University of North Carolina at Chapel Hill have recently introduced deschloroclozapine (DCZ), a new chemogenetic actuator that acts rapidly and is selective, high-affinity, metabolically stable and brain-penetrable. This new actuator, presented in a paper published in Nature Neuroscience, could eventually be used to rapidly induce reversible changes in the working memory and behavior of animals and potentially even humans.

"We investigated the selectivity as well as the rapidness of the DCZ action," Takafumi Minamimoto, one of the researchers who led the study, told MedicalXpress. "We first injected radiolabelled DCZ to animals expressing DREADDs locally within the brain and scanned them with positron emission tomography (PET)."

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