In neuroscience, chemogenetics is a fairly new area. The field investigates the use of selective ligands and synthetically derived receptors for temporary activation or deactivation of specific brain areas. Also known as Designer Receptors Exclusively Activated by Designer Drugs (DREADDS) – these receptors now find wide use in neuroscience and biology to modify neural activity and behavior temporarily.
Meanwhile, clozapine-N-oxide (CNO) is the most commonly used chemogenetic actuator so far used in DREADD implementation. While the actuator has served to be sometimes valuable in neuroscience studies, it has a number of drawbacks and limitations. This includes slow action and possible side-effects associated with its back-metabolism into clozapine. Clozapine is another actuator that has been extensive off-target effects.
For this, researchers at University of North Carolina and the National Institute of Radiological Sciences have recently introduced a new chemogenetic actuator – deschloroclozapine. The new chemogenetic actuator acts rapidly, and possesses high-affinity, brain penetrable, is selective, and metabolically stable.
The new actuator is presented in a paper published in Nature Neuroscience. This new actuator could eventually be used to induce reversible changes rapidly in the working memory and behavior of animals and even humans.
“The researchers investigated the selectivity and rapidness of deschloroclozapine action,” said one of the researchers who led the study. The team first administered radiolabelled DCZ to animals to express DREADDS locally within the brain, and further examined them with positron emission tomography.
The new chemogenetic actuator tested on both mice and monkeys. Thereafter, the neural activity of both animals recorded after DCZ injections employing two techniques: electrophysiology for monkeys and two-photon calcium imaging for mice.
The administered DCZ rapidly entered into the brain of the animals, selectively binding and occupying DREADDs.