Intra-hippocampal administration of ZIP alleviates depressive and anxiety-like responses in an animal model of posttraumatic stress disorder

Background: Given that impairment of fear extinction has been implicated in the pathogenesis of posttraumatic stress disorder (PTSD), effective pharmacological interventions that facilitate fear extinction may provide alternative strategies to conventional treatment. It is generally accepted that the zeta inhibitory peptide (ZIP), a controversial inhibitor of protein kinase M zeta (PKM zeta), could erase certain types of previously established long-term memories. However, it is unclear whether ZIP administration may alleviate PTSD-associated depressive and anxiety-like abnormalities. Methods: Here we developed a re-stressed single-prolonged stress (SPS) paradigm, a modified prevalent animal model of PTSD, and assayed the expressions of PKM zeta in the hippocampus after SPS procedure. Next, Seven days prior to re-stress, ZIP was injected into the hippocampus, and the depressive and anxiety-like behavior was examined by the subsequent forced swim (FS), open-field and elevated plus maze (EPM) test. Results: Rats given ZIP prior to FS exhibited a reduction of immobility time in FS test, and more open arms (OA) entries and longer OA duration in EPM. They also spent longer time in the center of the open field. Conclusions: Our results suggested that re-stressed SPS could reproduce behavioral alteration similar to that observed in patients with PTSD, and these behavioral symptoms co-morbid with PTSD could be effectively alleviated by the intro-hippocampal administration of ZIP.