Effect of 5-HT 2C receptor agonist and antagonist on chronic unpredictable stress (CUS) - Mediated anxiety and depression in adolescent Wistar albino rat: Implicating serotonin and mitochondrial ETC-I function in serotonergic neurotransmission.

Anxiety and depression are among the major neuropsychiatric disorders worldwide, and yet the etiologies of these disorders remain unclear to date. Chronic unpredictable stress (CUS) procedure mimics several behavioral characteristics such as anxiety and depression in rodents. Using this animal model, we have attempted to understand the serotonergic system in the hippocampus and prefrontal cortex, while using the 5-HT _2C R agonist and antagonist in evaluating 5-HT _2C receptor neurotransmission. A decrease in serotonin (5-HT) level, tryptophan hydroxylase-2 activity and, 5-HT _2C R receptor protein down-regulation in the CUS exposed group, explains the involvement of 5-HT and 5-HT _2C R neurotransmission in the genesis of anxiety and depression. Besides, the oxidative stress - attenuated electrolyte imbalance via decrease ATPase pump activity, and compromised oxidative phosphorylation via decrease ETC-I activity are some of the underlying factors affecting neuronal cell survival and serotonergic neurotransmission. To complement our finding, altered behavioral performance scored in the open field test, elevated plus maze test, and the forced swim test, when exposed to CUS is indicative or consistent with anxiety, depression, emotional and locomotor status of the animals. Keeping these findings in mind, treatment with 5-HT _2C R agonist (1-Methylpsilocin at 0.7 mg/kg), and 5-HT _2C R antagonist (RS-102221 hydrochloride at 1 mg/kg) displayed varying results. One prominent finding was the anxiolytic ability of the 5-HT _2C R agonist and the anti-depressive ability of the 5-HT _2C R antagonist on the 7th-day treatment. Though the exact mechanism of action is not clear, their ability to equilibrate brain redox status, restoring Ca ²⁺ level via Ca ²⁺ ATPase pump activity, and sustaining the mitochondrial bioenergetics can all be accounted for facilitating neurogenesis and the serotonergic system.
Competing Interests: Declaration of Competing Interest The authors declare that there is no conflict of interest to reveal.
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