Ketamine, a rapid antidepressant for treatment-resistant depression, requires functional opioid receptors to produce its effects, but it does not act as an opioid itself. In rodent models, blocking opioid receptors prevented ketamine's antidepressant-like behavioral and cellular effects, while activating opioid receptors alone caused hedonic responses and failed to alleviate anhedonia. Ketamine's cellular actions were mimicked by an NMDA receptor antagonist but not by a μ-opioid agonist. The findings suggest that ketamine's antidepressant action depends on both NMDA and opioid receptor signaling, with opioid receptors playing a permissive role rather than mediating the effects directly.
A new enzyme-based method called CaST (Ca2+-activated Split-TurboID) biochemically tags cells with elevated calcium levels in living animals within 10 minutes, without requiring implants or light delivery. The signal increases with calcium concentration and labeling time, acting as a time-gated integrator of calcium activity. Unlike transcriptional reporters that take hours, CaST allows immediate read-out after activity labeling. The approach was used to tag prefrontal cortex neurons activated by psilocybin in untethered mice, and the CaST signal correlated with psilocybin-induced head-twitch responses.