TY - JOUR
T1 - GLYX-13 Produces Rapid Antidepressant Responses with Key Synaptic and Behavioral Effects Distinct from Ketamine
AU - Liu, Rong Jian
AU - Duman, Catharine
AU - Kato, Taro
AU - Hare, Brendan
AU - Lopresto, Dora
AU - Bang, Eunyoung
AU - Burgdorf, Jeffery
AU - Moskal, Joseph
AU - Taylor, Jane
AU - Aghajanian, George
AU - Duman, Ronald S.
N1 - Funding Information:
This work is supported by NIMH R37MH45481 (RSD), NIMH R01MH93897 (RSD), a research grant from Naurex, the State of Connecticut, and Yale University. R.S. Duman has consulted and/or received research support from Naurex, Lilly, Forest, Johnson & Johnson, Taisho, and Sunovion; J.R. Moskal is the founder and has stock in Naurex, Inc; he also receives financial compensation as a consultant. J.S. Burgdorf is a consultant for Naurex, Inc., and has received financial compensation and stock. The remaining authors declare no conflict of interest.
Publisher Copyright:
© 2017 American College of Neuropsychopharmacology.
PY - 2017/5/1
Y1 - 2017/5/1
N2 - 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-HT 2A receptor. Behavioral studies further demonstrate that GLYX-13 does not influence 5-HT 2 receptor 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-HT 2 receptor 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.
AB - 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-HT 2A receptor. Behavioral studies further demonstrate that GLYX-13 does not influence 5-HT 2 receptor 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-HT 2 receptor 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=84991712864&partnerID=8YFLogxK
U2 - 10.1038/npp.2016.202
DO - 10.1038/npp.2016.202
M3 - Article
C2 - 27634355
AN - SCOPUS:84991712864
VL - 42
SP - 1231
EP - 1242
JO - Neuropsychopharmacology
JF - Neuropsychopharmacology
SN - 0893-133X
IS - 6
ER -