Depression is a common mental disorder characterized by persistent low mood, anhedonia, and cognitive impairment, seriously limiting psychosocial functioning and diminishing quality of life. The World Health Organization has predicted that major depression will become the leading cause of global disease burden by 2030 [1]. Current first-line pharmacological interventions, predominantly selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors, demonstrate significant limitations: therapeutic effects typically emerge only after 4-6 weeks of continuous administration, while part of patients exhibit inadequate response to initial treatment [[2], [3], [4]]. Furthermore, these conventional antidepressants carry substantial side effects including emotional blunting, weight gain and sexual dysfunction [[5], [6], [7]]. Thus, there is an urgent need to develop genuinely novel and rapid-acting therapeutics for depression.

Bufotenidine, along with other tryptamines including serotonin and bufotenine, is a naturally occurring indolealkylamine found in the toxic secretions of Bufo gargarizans Cantor or Bufo melanostictus Schneider [8]. As bioactive components of traditional Chinese medicine Chansu, tryptamines have shown cardiotonic, analgesic, and anti-inflammatory properties [[9], [10], [11], [12]]. Clinical studies have implicated tryptamines in the modulation of neuropsychiatric conditions, with observational data suggesting correlations between elevated endogenous levels of this compound and symptom severity in depression, schizophrenia, and autism spectrum disorder [13,14]. However, the role of bufotenidine against depression has not yet been investigated comprehensively.

AMPA glutamate receptors (AMPARs), heterotetrameric ligand-gated ion channels, predominantly composed of GluA1-GluA4 subunits, mediate a majority of excitatory neurotransmission in the central nervous system and are critical orchestrators of synaptic plasticity [15]. Dysfunction in AMPARs has been linked to depression. Preclinical studies revealed significant reduction in synaptosomal GluA1 levels, correlating with diminished dendritic complexity in the hippocampal CA1 and basal lateral amygdala regions, as well as reduced spine density in chronic stress-induced depressive mouse model [16]. These deficits were mechanistically linked to aberrant astrocyte signaling [17]. Persistent phosphorylation of GluA1 at Ser831 and Ser845 that enhances receptor conductance and synaptic retention, has been shown to mediate rapid antidepressant effects in rodent models [[18], [19], [20]]. Increased expression of surface GluA1 and GluA2 subunits in the ventral hippocampus rescued chronic social defeat stress (CSDS)-induced synaptic and depressive-like behavioral impairment [21].

Neuron-astrocyte crosstalk plays crucial roles in maintaining brain homeostasis and depression pathogenesis [22,23]. Neurons transferred lipotoxic fatty acid to astrocytes for detoxification, thereby mitigating neuronal oxidative stress and apoptosis [24]. In addition, rescue of astrocyte activity restored synaptic plasticity and learning and memory in mice with Alzheimer's disease [25,26]. The mechanisms by which neurons regulate astrocytic function in depression remain poorly characterized. Intriguingly, CSDS induced astrocyte loss of the hippocampus and medial prefrontal cortex region in depression [27]. Perimenopausal depression-like behaviors were alleviated through inhibiting ferroptosis in astrocytes of hypothalamus [28], implying that astrocyte ferroptosis participates in the pathogenesis of depression.

Here, we evaluated the antidepressant effect of bufotenidine and further investigated the mechanism. Bufotenidine significantly ameliorated corticosterone-induced depressive-like behaviors in mice. Bufotenidine directly bound to neuronal GluA1 to attenuate astrocyte ferroptosis. During this process, bufotenidine-GluA1 binding downregulated mTOR signaling and activated autophagy, followed by reduced lipid release from neurons to astrocytes.