Administration of moclobemide facilitates fear extinction and attenuates anxiety‐like behaviors by regulating synaptic‐associated proteins in a rat model of post‐traumatic stress disorder

Abstract

Post‐traumatic stress disorder (PTSD) is a long‐lasting mental disorder and accompanied by worse fear extinction. Enhanced fear memory or poor fear extinction are typical features of PTSD. Dysfunction of the serotonergic neurotransmitter system is involved in numerous mental and behavioral disorders. Monoamine oxidase A (MAOA) is important in the metabolism of serotonin and play an important role in behavious. The aim of this study was to explore the change of MAOA and effect of MAOA on fear memory in PTSD. We used single prolonged stress (SPS) to create animal model of PTSD. A startle/fear box and elevated plus maze were used to observe fear memory and anxiety level, respectively. We examined the expression of MAOA and synaptic marker protein, as well as the immunological activity of MAOA in the infralimbic cortex (IL) area, which is a critical brain region involved in emotions, especially fear regulation. We found increased anxiety‐like behavior, dysfunction in fear extinction, and increased MAOA in SPS rats. After treatment with moclobemide (a selective inhibitor of MAOA), SPS rats showed significantly improved fear memory and decreased anxiety‐like behavior, which indicated that moclobemide could reverse fear extinction deficit and attenuate abnormally increased levels of anxiety caused by SPS in short term. On the contrary, decreased PSD‐95 and SYN1 expression in the IL region were also reversed by moclobemide. These results suggest that increased MAOA play a negative role in fear extinction and levels of anxiety in PTSD, which may be involved in change in PSD‐95 and SYN1.

Identification of a Potent and Selective Human Monoamine Oxidase-A Inhibitor, Glycitein, an Isoflavone Isolated fromPueraria lobataFlowers

“…Increased ROS leads to the degeneration of striatal neurons, while DOPAC induces α-synuclein aggregation, a pathological hallmark of the PD brains. , Also, increased MAO-B activity is observed in AD brains . Recent studies showed that moclobemide, a clinically approved MAO-A inhibitor for depression, significantly reduced anxiety-like behavior and enhanced fear memory in stressed mice, facilitated smoking cessation and improved anti-Parkinson effect of levodopa treatment . Beside a neurological role, MAO-A inhibition could protect the myocardial damage due to the ROS generation in peripheral tissues resulting from the MAO-A oxidation and suppress cell growth, proliferation, and metastasis of cancer cells such as prostate cancer .…”

Systematic Review and Methodological Considerations for the Use of Single Prolonged Stress and Fear Extinction Retention in Rodents

“…With these overall aims, we selected the SPS model, one of the most popular paradigms in the field of preclinical PTSD modeling, combined with fear extinction retention as a test for behavioral changes relevant to PTSD to conduct an in depth methodological review to determine sources of variability and develop optimization guidelines to enhance reproducibility across laboratories. SPS is widely applied to probe multiple PTSD-relevant phenotypes (behavioral and physiological) and putative trauma mechanisms [oxytocin regulation, the neuropeptide Y (NPY) system, synaptic protein expression, and memory function] (Serova et al, 2019;Hirota et al, 2020;Liu et al, 2020;Nwokafor et al, 2020;Xiao et al, 2020). This model has a number of elements that support its adoption including: (1) SPS has defined core features that support a capacity for reproducibility (i.e., restraint for 2 h, forced swim for 20 min, and ether until loss of consciousness to promote activation of the HPA axis; Yamamoto et al, 2009;Lisieski et al, 2018), (2) the use of SPS in mice and rats, (3) its initial development to probe PTSD-specific phenotypes including glucocorticoid receptor hypersensitivity and disrupted fear extinction, (4) its stress/incubation timeline that allows manipulation at various intervention points, and (5) SPS does not rely on post-hoc sorting of susceptible animals (e.g., social defeat).…”

The effects of orexin‐A and orexin receptors on anxiety‐ and depression‐related behaviors in a male rat model of post‐traumatic stress disorder

“…Flores et al, 2014; Johnson, Molosh, et al, 2012; Soya et al, 2017; Strawn et al, 2010; Wilson et al, 2019; Yu et al, 2016). In our previous research, we demonstrated that significant behavioral changes in rats 7 days after SPS stimulation (Ding et al, 2017; F. Han et al, 2014; L. Wen et al, 2017; Xiao et al, 2020). Therefore, we chose this timepoint (7 days after SPS) as the time point for behavioral tests in the present study.…”

“…In our previous research, we demonstrated that significant behavioral changes in rats 7 days after SPS stimulation (Ding et al, 2017;F. Han et al, 2014;Xiao et al, 2020). Therefore, we chose this timepoint (7 days after SPS) as the time point for behavioral tests in the present study.…”