title: Administration of N-acetylserotonin and melatonin alleviate chronic ketamine-induced behavioural phenotype accompanying BDNF-independent and dependent converging cytoprotective mechanisms in the hippocampus.
abstract: Though growing evidence implicates both melatonin (MLT) and its immediate precursor N-acetylserotonin (NAS) in the regulation of hippocampal neurogenesis, their comparative mechanistic relationship with core behavioural correlates of psychiatric disorders is largely unknown. To address this issue, we investigated the ability of these indoleamines to mitigate the behavioral phenotypes associated with NMDA-receptor (NMDAR) hypofunction in mice. We demonstrated that exogenous MLT and NAS treatments attenuated the NMDAR antagonist (ketamine) induced immobility in the forced swim test (FST) but not the classical striatum-related hyperlocomotor activity phenotype. The MLT/NAS-mediated protection of the phenotype in FST could be correlated to the ability of these indoleamines to counteract the deleterious effects of chronic ketamine on pro-survival molecular events by restoring the activities in MEK-ERK and PI3K-AKT pathways in the hippocampus. MLT seems to modulate these pathways by promoting accumulation of the mature form of BDNF above the control (vehicle-treated) levels, perhaps via MLT receptor-dependent mechanisms and in the process overcoming the ketamine-induced down-regulation of BDNF. In contrast, NAS appears to partly restore the ketamine-induced decrease of BDNF to the control levels. In spite of this fundamental difference in modulating BDNF levels in the upstream events, both MLT and NAS seem to overlap in the TrkB-induced downstream pro-survival mechanisms in the hippocampus, providing protection against NMDAR-hypofunction related cellular events. Perhaps, this also signifies the physiological importance of robust MLT synthesizing machinery that converts serotonin to MLT, in ensuring positive impact on hippocampus-related symptoms in psychiatric disorders.
authors.affiliation: Chronic Disease Biology Group, Institute of Molecular Medicine, 254 Okhla Industrial Estate, Phase-3, New Delhi 110020, India.
authors.forename: Arnab
authors.initials: A
authors.lastname: Choudhury
authors.affiliation: Division of Pharmacology, CSIR-Central Drug Research Institute, Lucknow 226031 U.P, India; Academy of Scientific and Innovative Research (AcSIR), New Delhi 110001, India.
authors.forename: Seema
authors.initials: S
authors.lastname: Singh
authors.affiliation: Division of Pharmacology, CSIR-Central Drug Research Institute, Lucknow 226031 U.P, India.
authors.forename: Gautam
authors.initials: G
authors.lastname: Palit
authors.affiliation: Division of Pharmacology, CSIR-Central Drug Research Institute, Lucknow 226031 U.P, India; Academy of Scientific and Innovative Research (AcSIR), New Delhi 110001, India. Electronic address: shubha_shukla@cdri.res.in.
authors.forename: Shubha
authors.initials: S
authors.lastname: Shukla
authors.affiliation: Chronic Disease Biology Group, Institute of Molecular Medicine, 254 Okhla Industrial Estate, Phase-3, New Delhi 110020, India. Electronic address: surajitg@immindia.org.
authors.forename: Surajit
authors.initials: S
authors.lastname: Ganguly
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D006624:Hippocampus / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D007649:Ketamine / Q000633:toxicity; D008550:Melatonin / Q000494:pharmacology*; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects* / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010641:Phenotype; D011897:Random Allocation; D020813:Receptor, trkB / Q000378:metabolism; D044094:Receptors, Melatonin / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012701:Serotonin / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D018696:Neuroprotective Agents; D044094:Receptors, Melatonin; D016194:Receptors, N-Methyl-D-Aspartate; D012701:Serotonin; D007649:Ketamine; D020813:Receptor, trkB; D008550:Melatonin; C006389:N-acetylserotonin
keywords: BDNF; Hippocampus; Melatonin; N-acetylserotonin; NMDA receptor; Psychiatry