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

Abstract

BackgroundGiven 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 (PKMζ), 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.MethodsHere we developed a re-stressed single-prolonged stress (SPS) paradigm, a modified prevalent animal model of PTSD, and assayed the expressions of PKMζ 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.ResultsRats 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.ConclusionsOur 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.

Activation of Sigma-1 receptor ameliorates anxiety-like behavior and cognitive impairments in a rat model of post-traumatic stress disorder

“…In this study, rats exposed to RSPS paradigm exhibited PTSD-like behaviors as In the OF, EPM and MWM test, the RSPS group rats showed a significant anxiety-like behaviors and cognitive impairments compared with controls after RSPS exposure, which was consistent with our and other previous studies [30,32,33].…”

“…The apparatus was made with black Plexiglas measuring 50 × The elevated plus maze (EPM) test was performed as previously described [32]. Morris water maze (MWM) was performed to evaluate the rat spatial learning and memory.…”

New neurons restore structural and behavioral abnormalities in a rat model of PTSD

“…Several previous studies have observed behavioral effects of SPS that persist for several weeks. Increased anxiodepressive behavior is seen shortly after SPS and persists for at least 2-3 weeks (Ji et al, 2014;Khan & Liberzon, 2004;Lin, Tung, & Liu, 2016;Miao et al, 2014;Patki et al, 2014;Peng et al, 2010;Takahashi, Morinobu, Iwamoto, & Yamawaki, 2006), consistent with the increase in anxietylike behavioral changes observed here 1-2 weeks after stress. We found that elevated plus maze behavior and NSF returned to normal within 5 weeks of SPS in normal (wild type) rats.…”

“…The current findings indicate that cells born up to a week after a 1‐day stress continue to show decreased survival. L‐type calcium channels containing the Ca V 1.2 subunit, which are upregulated in the hippocampus following SPS and chronic stress and have been implicated in PTSD (Ji et al, ; Krzyzewska et al, ; Maigaard, Hageman, Jørgensen, Jørgensen, & Wörtwein, ), may be an important part of the mechanism regulating the survival of new neurons following SPS. A recent study found that cells born at the end of chronic stress period showed increased survival relative to cells born in unstressed rats (De Miguel, Haditsch, Palmer, Azpiroz, & Sapolsky, ), suggesting that the removal of stress may have a positive effect on survival of a cohort of neurons maturing during the poststress recovery period.…”

Sigma-1 receptor activation ameliorates anxiety-like behavior through NR2A-CREB-BDNF signaling pathway in a rat model submitted to single-prolonged stress

“…Elevated plus maze test. The elevated plus maze (EPM) test was performed after OFT as previously described (28). Briefly, the EPM apparatus is made up of two opposing open and two opposing closed arms (50 cm arms, 50 cm off the ground).…”