Off-target effects of PLX5622 revealed: mixing microglial function in anesthesia and addiction withdrawal

Microglia have gained increasing attention as important regulators in the brain. Acute microglial depletion using the colony-stimulating factor 1 receptor (CSF1R) inhibitor, PLX5622, has become a popular approach to uncover microglial function. PLX5622 treatment has been recently shown to significantly promote anesthetic emergence. In characterizing underlying mechanisms, we found that PLX5622 treatment did not change the global neuronal activity during anesthesia, but robustly enhanced anesthetic metabolism. Moreover, PLX5622 dramatically induced the expression of hepatic enzymes that extensively modify xenobiotic and endobiotic metabolism. Blocking increased enzymatic activity significantly reduced the arousal-promoting effects of PLX5622 in anesthesia, irrespective of microglial elimination. In addition, we demonstrate that enhanced drug metabolism also contributed to PLX5622-induced attenuation in nicotine-withdrawal anxiety. By revealing previously unrecognized effects of PLX5622, our findings raise caution in interpreting data generated from PLX5622 treatment and bring forward the need for designing more specific CSF1R inhibitors.