Short-Term Exercise Improved Stress-Induced Depressive-Like Behavior and Affected the Expression of TPH2 and P38 but not the Cannabinoid CB1 Receptor and JNK

Abstract

Background: Major Depressive Disorder (MDD) is a disabling multifactorial neuropsychiatric disorder in which several neurobiological systems and signaling pathways are involved. Physical activity improves mood and displays antidepressant effects. However, the exact mechanism underlying these effects from different exercise sessions has not been comprehensively studied. The aim of this study was to investigate the effects of short-term exercise on depressive behaviors and also its possible modulatory effects on three critical pathways, which are dysregulated in depressive pathophysiology, including serotonergic tryptophan hydroxylase 2 (TPH2), mitogen-activated protein kinase (MAPK) including p38 and c-Jun N-terminal kinases (JNK), and cannabinoid receptor 1 (CB1) systems in the stress-induced rat model of depression. Methods: Following seven weeks of chronic unpredictable mild stress (CUMS) protocol, male Wistar rats were exposed to 60 minutes of treadmill-running exercise (10 min preparatory; 50 min training session, 10 m/min) for five consecutive days. Then, the anti-depressive effects were evaluated by the forced swimming test (FST) and the open field test (OFT), and finally, rats were decapitated, and their prefrontal cortex (PFC) was extracted for further analysis. Results: The results showed that CUMS induced a significant increase in immobility time in the FST (p < 0.01), which was reversed by short-term exercise (p < 0.01), and a slight decrease in horizontal distance in the OFT. Moreover, CUMS increased the protein expressions of CB1 and p-JNK/JNK in PFC (p < 0.001), and no effect of exercise was observed on these markers (p > 0.05). Interestingly, we found that the CUMS-induced p-p38/p38 ratio increment was reversed by the training session (p < 0.001). Meanwhile, short-term exercise also significantly upregulated TPH2, whose level was diminished in CUMS rats. Conclusions: Our results reveal that short-term exercise alleviates depression behavior induced by chronic stress and improves the 5-hydroxytryptamine (5-HT) neurotransmission regulating enzyme, TPH2. In addition, the observed reduction of p38 phosphorylation may play a key modulatory role in the anti-depressive-like properties of short-term exercise, which needs further study to approve the exact mechanisms.