Ramelteon protects against social defeat stress-associated abnormal behaviors

• Published in: Pharmacology, biochemistry and behavior Vol. 241; p. 173794
• Main Authors: Chen, Chao-Wei, Yeh, Wei-Lan, Charoensaensuk, Vichuda, Lin, Chingju, Yang, Liang-Yo, Xie, Sheng-Yun, Lane, Hsien-Yuan, Lin, Chieh-Hsin, Wang, Yu-Wen, Tsai, Cheng-Fang, Lu, Dah-Yuu
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.08.2024
• Subjects: Animals; Anxiety - drug therapy; Anxiety - psychology; Anxiety-like behaviors; Behavior, Animal - drug effects; Hippocampus - drug effects; Hippocampus - metabolism; Indenes - pharmacology; Male; Melatonin - pharmacology; Melatonin receptors; Mice; Mice, Inbred C57BL; Monoamine Oxidase - metabolism; PTSD; Ramelteon; Receptor, Melatonin, MT1 - agonists; Receptor, Melatonin, MT1 - metabolism; Receptor, Melatonin, MT2 - agonists; Receptor, Melatonin, MT2 - metabolism; Receptors, Glucocorticoid - agonists; Receptors, Glucocorticoid - metabolism; Receptors, Melatonin - agonists; Receptors, Melatonin - metabolism; Social avoidance; Social Defeat; Stress Disorders, Post-Traumatic - drug therapy; Stress Disorders, Post-Traumatic - metabolism; Stress Disorders, Post-Traumatic - psychology; Stress, Psychological - drug therapy; Stress, Psychological - metabolism; PTSD; Melatonin receptors; Ramelteon; Social avoidance; Anxiety-like behaviors
• DOI: 10.1016/j.pbb.2024.173794
• ISSN: 0091-3057; 1873-5177

Psychological stress affects the neuroendocrine regulation, which modulates mental status and behaviors. Melatonin, a hormone synthesized primarily by the pineal gland, regulates many brain functions, including circadian rhythms, pain, sleep, and mood. Selective pharmacological melatonin agonist ramelteon has been clinically used to treat mood and sleep disorders. Posttraumatic stress disorder (PTSD) is a psychiatric condition associated with severe trauma; it is generally triggered by traumatic events, which lead to severe anxiety and uncontrollable trauma recall. We recently reported that repeated social defeat stress (RSDS) may induce robust anxiety-like behaviors and social avoidance in mice. In the present study, we investigated whether melatonin receptor activation by melatonin and ramelteon regulates RSDS-induced behavioral changes. Melatonin treatment improved social avoidance and anxiety-like behaviors in RSDS mice. Moreover, treatment of the non-selective MT1/MT2 receptor agonist, ramelteon, markedly ameliorated RSDS-induced social avoidance and anxiety-like behaviors. Moreover, activating melatonin receptors also balanced the expression of monoamine oxidases, glucocorticoid receptors, and endogenous antioxidants in the hippocampus. Taken together, our findings indicate that the activation of both melatonin and ramelteon regulates RSDS-induced anxiety-like behaviors and PTSD symptoms. The current study also showed that the regulatory effects of neuroendocrine mechanisms and cognitive behaviors on melatonin receptor activation in repeated social defeat stress. •Melatonin treatment improved social avoidance and anxiety-like behaviors in RSDS mice.•Ramelteon markedly ameliorated RSDS-induced social avoidance and anxiety-like behaviors.•Activation of melatonin receptors balanced the expression of monoamine oxidases, glucocorticoid receptors, and endogenous antioxidants in the hippocampus.•Ramelteon protects RSDS-elicited behavioral changes through the MT1 receptor in the hippocampus.