(2R,6R)-HNK attenuates negative emotional behaviors and synaptic plasticity deficits via GluA1 in rats exposed to single prolonged stress and foot shock.

Abstract

BACKGROUND: Post-traumatic stress responses are debilitating psychiatric conditions triggered by exposure to traumatic events. Dysregulation of the glutamatergic system, particularly in circuits governing negative emotional responses, plays a central role in pathogenesis of stress-related disorders. However, the specific contribution of glutamate receptor subtypes remains poorly defined. METHODS: This study examined the role of GluA1-containing AMPA receptors (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors) within the hippocampus (HIP), prefrontal cortex (PFC), and amygdala (AMY) in mediating stress-induced negative affective behavioral disturbances in the single prolonged stress plus foot-shock (SPS&S) paradigm. The therapeutic potential of (2R,6R)-hydroxynorketamine ((2R,6R)-HNK) was further evaluated. RESULTS: SPS&S exposure, particularly following GluA1 knockdown, exacerbated anxiety- and depression-like behaviors, reduced GluA1 expression and associated synaptic protein and mRNA levels in the HIP and PFC, and increased their expression in the AMY. Treatment with (2R,6R)-HNK significantly attenuated both SPS&S- and siRNA-induced behavioral abnormalities, restored GluA1-dependent PI3K/AKT signaling, and ameliorated synaptic deficits. These restorative effects were most prominent in the HIP and PFC, with minimal changes observed in the AMY. CONCLUSION: These findings demonstrate that GluA1-mediated signaling is critical for the regulation of emotion and synaptic plasticity in the SPS&S model. By normalizing GluA1 dynamics and synaptic function, (2R,6R)-HNK shows promise as a targeted therapeutic agent for alleviating negative affect associated with the SPS&S mode.