4-Methoxycinnamic acid ameliorates post-traumatic stress disorder-like behavior in mice by antagonizing the CRF type 1 receptor

Aims: Posttraumatic stress disorder (PTSD) is a debilitating neuropsychiatric illness caused by traumatic or life-threatening events and manifesting as various symptoms, including intrusive re-experiences of trauma, avoidance behaviors, hyperarousal, and negative changes in perception and mood. Main methods: Current monoamine-based medications commonly exhibit limited efficacy and significant side effects, which hamper their clinical utility. To address this unmet need, we explored 4-methoxycinnamic acid (4-MCA) as a potential novel treatment for PTSD in a single prolonged stress (SPS)-induced animal model. Key findings: Administration of 4-MCA (3 and 10 mg/kg, p.o.) significantly mitigated anxiety-like behaviors, alleviated depression-like behaviors, and improved cognitive function in an SPS-treated PTSD mouse model. Further, 4-MCA treatment effectively rectified the fear extinction deficits in the fear conditioning test. Molecular analyses revealed that 4-MCA normalized the elevated corticotropin-releasing hormone (CRH) levels as well as the phosphorylation of protein kinase A (PKA) and cAMP response element-binding protein (CREB) in the amygdala, a pivotal region for fear memory formation. Co-administration of 4-MCA and the CRFR1 antagonist antalarmin at subeffective doses facilitated fear memory extinction. Significance: These findings suggest that 4-MCA alleviates SPS-induced PTSD-like behaviors by regulating the CRH-CRFR1-PKA-CREB signaling pathway in the amygdala, and that 4-MCA may be a potential candidate for future PTSD treatment.