title: GLYX-13 Produces Rapid Antidepressant Responses with Key Synaptic and Behavioral Effects Distinct from Ketamine.
abstract: GLYX-13 is a putative NMDA receptor modulator with glycine-site partial agonist properties that produces rapid antidepressant effects, but without the psychotomimetic side effects of ketamine. Studies were conducted to examine the molecular, cellular, and behavioral actions of GLYX-13 to further characterize the mechanisms underlying the antidepressant actions of this agent. The results demonstrate that a single dose of GLYX-13 rapidly activates the mTORC1 pathway in the prefrontal cortex (PFC), and that infusion of the selective mTORC1 inhibitor rapamycin into the medial PFC (mPFC) blocks the antidepressant behavioral actions of GLYX-13, indicating a requirement for mTORC1 similar to ketamine. The results also demonstrate that GLYX-13 rapidly increases the number and function of spine synapses in the apical dendritic tuft of layer V pyramidal neurons in the mPFC. Notably, GLYX-13 significantly increased the synaptic responses to hypocretin, a measure of thalamocortical synapses, compared with its effects on 5-HT responses, a measure of cortical-cortical responses mediated by the 5-HT2Areceptor. Behavioral studies further demonstrate that GLYX-13 does not influence 5-HT2receptor induced head twitch response or impulsivity in a serial reaction time task (SRTT), whereas ketamine increased responses in both tests. In contrast, both GLYX-13 and ketamine increased attention in the SRTT task, which is linked to hypocretin-thalamocortical responses. The differences in the 5-HT2receptor synaptic and behavioral responses may be related to the lack of psychotomimetic side effects of GLYX-13 compared with ketamine, whereas regulation of the hypocretin responses may contribute to the therapeutic benefits of both rapid acting antidepressants.
authors.affiliation: Departments of Psychiatry and Neurosciences, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Rong-Jian
authors.initials: RJ
authors.lastname: Liu
authors.affiliation: Departments of Psychiatry and Neurosciences, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Catharine
authors.initials: C
authors.lastname: Duman
authors.affiliation: Departments of Psychiatry and Neurosciences, Yale University School of Medicine, New Haven, CT, USA.|Sumitomo Dainippon Pharma Co, Suita, Osaka, Japan.
authors.forename: Taro
authors.initials: T
authors.lastname: Kato
authors.affiliation: Departments of Psychiatry and Neurosciences, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Brendan
authors.initials: B
authors.lastname: Hare
authors.affiliation: Departments of Psychiatry and Neurosciences, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Dora
authors.initials: D
authors.lastname: Lopresto
authors.affiliation: Departments of Psychiatry and Neurosciences, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Eunyoung
authors.initials: E
authors.lastname: Bang
authors.affiliation: Falk Center for Molecular Therapeutics, Department of Biomedical Engineering, Northwestern University, Evanston IL, USA.
authors.forename: Jeffery
authors.initials: J
authors.lastname: Burgdorf
authors.affiliation: Falk Center for Molecular Therapeutics, Department of Biomedical Engineering, Northwestern University, Evanston IL, USA.|Naurex, Inc., Evanston, IL, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Moskal
authors.affiliation: Departments of Psychiatry and Neurosciences, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Jane
authors.initials: J
authors.lastname: Taylor
authors.affiliation: Departments of Psychiatry and Neurosciences, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: George
authors.initials: G
authors.lastname: Aghajanian
authors.affiliation: Departments of Psychiatry and Neurosciences, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Ronald S
authors.initials: RS
authors.lastname: Duman
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects*; D007649:Ketamine / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D008810:Mice, Inbred C57BL; D009842:Oligopeptides / Q000008:administration & dosage / Q000494:pharmacology*; D017397:Prefrontal Cortex / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects*; D013569:Synapses / Q000187:drug effects*
chemical_list: D000928:Antidepressive Agents; D009842:Oligopeptides; D016194:Receptors, N-Methyl-D-Aspartate; D007649:Ketamine; C507283:GLYX-13 peptide