Oxytocin Protects Against Corticosterone-Induced DA Dysfunction: An Involvement of the PKA/CREB Pathway

Chronic stress disrupts dopamine (DA) transmission, adversely affecting mood and contribution to neuropsychiatric disorders like ADHD, autism, schizophrenia, anxiety, depression, and drug addiction. The neuropeptide oxytocin (OXT) plays a key role in social cognition, bonding, attachment, and parenting behaviors. In addition, OXT can modulate the activity of the HPA axis, counteracting the effects of stress, and alleviating fear and anxiety. However, whether OXT can mitigate stress-induced DA dysfunction and the underlying mechanisms remains unclear. This study investigated the neuroprotective effects of OXT on corticosterone (CORT) induced DA dysfunction in the neuroblastoma cell line SH-SY5Y. The results revealed that CORT decreases the levels of intracellular signaling molecules associated with DA function, including phosphorylated tyrosine hydroxylase (pTH), phosphorylated cAMP response element-binding protein (pCREB), and protein kinase A (PKA). Interestingly, pretreatment with OXT mitigated CORT-induced DA dysfunction through its potent PKA activator properties. In addition, the neuroprotective effect of OXT was abolished by atosiban (an OXT receptor antagonist) or H89 (a PKA inhibitor). Our results suggest that OXT protects dopaminergic neuroblastoma cells from CORT-induced DA dysfunction, potentially through the involvement of oxytocin receptors and the PKA/CREB signaling pathway. These findings contribute to the understanding of the neurobiological mechanisms underlying stress resilience and highlight potential pathways for developing targeted treatments that leverage the neuroprotective properties of OXT to address disorders characterized by DA dysregulation and impaired stress responses.