Effects of Single Bolus Exposure to Propofol on Depression-like Behavior in a Chronic Unpredictable Mild Stress Model in Mice

BACKGROUND: Depression is a prevalent psychiatric disorder linked to excitatory/inhibitory neurotransmission imbalance, particularly in the medial prefrontal cortex (mPFC). Propofol, a γ-aminobutyric acid type A (GABA A ) receptor agonist, induces rapid mood improvements clinically, yet its antidepressant-like effects and underlying mechanisms remain unclear. METHODS: Network pharmacology was used to identify propofol-related targets linked to excitatory/inhibitory balance. Male mice exposed to chronic unpredictable mild stress (CUMS) received a single intraperitoneal injection of propofol. Depressive-like behaviors were assessed using the open field, tail suspension, and forced swim tests. γ-Aminobutyric acid-mediated (GABAergic) and glutamatergic signaling in the mPFC was evaluated by Western blotting, immunofluorescence, and fiber photometry calcium imaging. Optogenetic manipulation of mPFC GABAergic interneurons was performed to test their causal involvement. RESULTS: In both male and female mice, compared with the control group, propofol (50 mg · kg -1 ) significantly reduced CUMS-induced depression-like behaviors, showing optimal efficacy in the open field test, tail suspension test, forced swim test, and sucrose preference test. Propofol increased mPFC GABAergic neuron excitability while suppressing glutamatergic activity. It also restored CUMS-induced reductions in GABAergic (glutamate decarboxylase [GAD] 65, GAD67, vesicular GABA transporter [VGAT], GABA transporter 3 [GAT3], γ-aminobutyric acid type A receptor subunit alpha 1 [GABA A α1], γ-aminobutyric acid type A receptor subunit γ 2 [GABA A γ2]) and glutamatergic (glutamate ionotropic receptor AMPA type subunit 1 [GluA1], metabotropic glutamate receptor 5 [mGlu5], vesicular glutamate transporter 1 [VGLUT1]) protein expression. Pharmacologic inhibition of GABA A receptors with the antagonist bicuculline abolished propofol's antidepressant effects. Optogenetic activation of GABAergic interneurons at 10 Hz enhanced propofol's antidepressant effects, whereas inhibition attenuated them. CONCLUSIONS: Propofol produces rapid antidepressant-like effects through activating the GABA A receptors and restoring the γ-aminobutyric acid/glutamate balance. These findings suggest that propofol could be a useful tool for investigating the mechanisms of fast-acting antidepressant.