The location, physiology, pathology of hippocampus Melatonin MT₂ receptor and MT₂-selective modulators

Melatonin, a neurohormone secreted by the pineal gland and regulated by the suprachiasmatic nucleus (SCN) of the hypothalamus, is synthesized and directly released into the cerebrospinal fluid (CSF) of the third ventricle (3rdv), where it undergoes rapid absorption by surrounding tissues to exert its physiological function. The hippocampus, a vital structure in the limbic system adjacent to the ventricles, plays a pivotal role in emotional response and memory formation. Melatonin MT₁ and MT₂ receptors are G protein-coupled receptors (GPCRs) that primarily mediate melatonin's receptor-dependent effects. In comparison to the MT₁ receptor, the widely expressed MT₂ receptor is crucial for mediating melatonin's biological functions within the hippocampus. Specifically, MT₂ receptor is implicated in hippocampal synaptic plasticity and memory processes, as well as neurogenesis and axogenesis. Numerous studies have demonstrated the involvement of MT₂ receptors in the pathophysiology and pharmacology of Alzheimer's disease, depression, and epilepsy. This review focuses on the anatomical localization of MT₂ receptor in the hippocampus, their physiological function in this region, and their signal transduction and pharmacological roles in neurological disorders. Additionally, we conducted a comprehensive review of MT₂ receptor ligands used in psychopharmacology and other MT₂-selective ligands over recent years. Ultimately, we provide an outlook on future research for selective MT₂ receptor drug candidates.