Chemogenetics (DREADDs)

Chemogenetics controls genetically targeted neurons through an engineered receptor that is activated only by an otherwise inert designer drug. The most common tools are DREADDs (Designer Receptors Exclusively Activated by Designer Drugs), mutated G-protein-coupled receptors engineered to ignore their native ligand and instead respond to a synthetic agonist such as clozapine-N-oxide, with excitatory and inhibitory variants coupling to different G-protein pathways.

Compared with optogenetics, chemogenetics needs no implanted light source and can modulate a whole population over minutes to hours with a single systemic dose, making it convenient for sustained manipulation. The trade-off is temporal coarseness and a lack of on-demand reversibility. It shares optogenetics' translational barriers of viral gene delivery and off-target concerns, sharpened by the finding that the agonist clozapine-N-oxide can back-metabolize to clozapine, a centrally active compound, which confounds interpretation. It remains primarily a research tool rather than a clinical therapy.