α7 Nicotinic Acetylcholine Receptor Activation Promotes Anxiety- and Depressive-Like Behaviors Associated With...

Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis is a central feature of stress-related affective disorders, and corticotropin-releasing hormone (CRH) neurons in the hypothalamic paraventricular nucleus (PVN) initiate neuroendocrine stress responses. Although the α7 nicotinic acetylcholine receptor (α7 nAChR) has been implicated in emotional regulation, its role in PVN CREB/CRH signaling and anxiety- and depressive-like behaviors remains unclear. Here, using male C57BL/6 mice, we found that pharmacological activation of α7 nAChR with PNU282987 induced anxiety- and depressive-like behaviors under control conditions and further exacerbated behavioral abnormalities following chronic restraint stress (CRS), without significantly affecting locomotor activity. PNU282987 also increased CREB phosphorylation and CRH expression in the PVN and elevated serum CRH, adrenocorticotropic hormone (ACTH), and corticosterone (CORT) levels. Conversely, in CRS mice, the α7 nAChR-preferring antagonist methyllycaconitine (MLA) increased sucrose preference, OFT center exploration, and EPM open-arm time while reducing TST immobility. These behavioral effects were accompanied by reduced PVN CREB phosphorylation and CRH expression and decreased serum CRH, ACTH, and CORT levels. Notably, α7 nAChR protein abundance in the PVN was not significantly altered by CRS or drug treatment, suggesting that functional receptor activation rather than receptor upregulation may drive downstream signaling. Moreover, the CREB-mediated transcription inhibitor 666-15 attenuated PNU282987-induced behavioral abnormalities, serum CRH elevation, and PVN CRH upregulation. These findings indicate that α7 nAChR activation promotes anxiety- and depressive-like behaviors associated with enhanced PVN CREB phosphorylation, CRH upregulation, and HPA axis hyperactivity. CREB-associated CRH signaling may therefore represent a neuroendocrine mechanism linking α7 nAChR activation to stress-related affective disturbances.