Major depressive disorder has emerged as one of the most prevalent mental disorders, however, a poor understanding of the pathological theories underlying the development of depression has hindered effective and satisfactory therapeutics (Li et al., 2021; Ren et al., 2020). Alternations in the neuroplasticity of specific neuronal populations and neural circuitry have been strongly implicated in the mechanism of depression (Ressler and Mayberg, 2007), and general anaesthetics known to manipulate a wide range of neuronal activities in the brain have shown important therapeutic potential for depression (Vutskits, 2018). While general anaesthesia, as a brief period of loss and recovery of consciousness, appears to result from a temporary interference with excitatory and inhibitory neural homeostasis, general anaesthetics are thought to be potent in initiating a long-lasting impact on neuronal structures and functions (Vutskits, 2012). Because of these observations, general anaesthetics have become a suitable candidate for antidepressant therapies.

New evidence has validated the antidepressant potential of general anaesthetics. The intravenous dissociative anaesthetic ketamine has the potential to provide effective and rapid relief of depressive symptoms, as well as to reduce suicidality in patients with and without other therapies (McGirr et al., 2015; Serafini et al., 2014). It has now been widely reported that ketamine could produce these rapid and sustained antidepressant effects via cellular and molecular targets (Singh et al., 2017; Zanos and Gould, 2018) or neural circuits regarding negative emotions (Cui et al., 2018; Yang et al., 2018). Moreover, commonly used anaesthetics in clinical practice, including propofol, nitrous oxide and isoflurane, also display antidepressant efficacy (Chen et al., 2021; Tadler and Mickey, 2018). Sevoflurane, with a safe profile and abilities to provide a relatively more steady and rapid induction and recovery course than other inhalational anaesthetics (Campbell et al., 1996), was also reported to produce rapid and durable antidepressant and neuroprotective effects with fewer adverse effects (Wang et al., 2020). These findings suggest that general anaesthetics are worth investigating for the treatment of depressive disorders.

As a component of the limbic system, the nucleus accumbens has been strongly implicated in the regulation of motivational behaviours (Francis and Lobo, 2017). Disruption of neuronal excitability and plasticity in the nucleus accumbens is believed to be the underlying mechanism of stress-induced depression and other mental disorders (McEwen et al., 2015; Shen et al., 2019). In recent studies, the activities of nucleus accumbens neurons were found to fluctuate during treatment with sevoflurane anaesthesia (Bao et al., 2021; Gui et al., 2021) and to be involved in the regulation of sevoflurane-induced loss and recovery of consciousness (Bao et al., 2021). Considering these findings, we proposed that the nucleus accumbens might play a role in the antidepressant-like effects of sevoflurane.

The present study aimed to validate the antidepressant effects of and to determine the most effective therapeutic conditions of sevoflurane. Combinations of genetically defined chemogenetics and behavioural assessment assays for depression and anxiety were applied to investigate the role of GABAergic (γ-aminobutyric acidergic) neurons of the nucleus accumbens in the antidepressant-like effects of sevoflurane. Furthermore, we found that inhaling 2.5% sevoflurane for 30 min could effectively alleviate depression- and anxiety-like behaviours for 48 h. Moreover, activating GABAergic neurons in the nucleus accumbens core, rather than the nucleus accumbens shell, mimicked the antidepressant effect of sevoflurane, whereas inhibition of these neurons abolished them, verifying a vital regulatory role for GABAergic neurons in the nucleus accumbens core. Considered together, these findings emphasize the antidepressant potential of sevoflurane and provide a novel neuronal mechanism underlying these effects.