PMID- 29133952
OWN - NLM
STAT- MEDLINE
DCOM- 20181217
LR  - 20210109
IS  - 1476-5578 (Electronic)
IS  - 1359-4184 (Linking)
VI  - 23
IP  - 1
DP  - 2018 Jan
TI  - Engaging homeostatic plasticity to treat depression.
PG  - 26-35
LID - 10.1038/mp.2017.225 [doi]
AB  - Major depressive disorder (MDD) is a complex and heterogeneous mood disorder, 
      making it difficult to develop a generalized, pharmacological therapy that is 
      effective for all who suffer from MDD. Through the fortuitous discovery of 
      N-methyl-D-aspartate receptor (NMDAR) antagonists as effective antidepressants, 
      we have gained key insights into how antidepressant effects can be produced at 
      the circuit and molecular levels. NMDAR antagonists act as rapid-acting 
      antidepressants such that relief from depressive symptoms occurs within hours of 
      a single injection. The mode of action of NMDAR antagonists seemingly relies on 
      their ability to activate protein-synthesis-dependent homeostatic mechanisms that 
      restore top-down excitatory connections. Recent evidence suggests that NMDAR 
      antagonists relieve depressive symptoms by forming new synapses resulting in 
      increased excitatory drive. This event requires the mammalian target of rapamycin 
      complex 1 (mTORC1), a signaling pathway that regulates synaptic protein 
      synthesis. Herein, we review critical studies that shed light on the action of 
      NMDAR antagonists as rapid-acting antidepressants and how they engage a neuron's 
      or neural network's homeostatic mechanisms to self-correct. Recent studies 
      notably demonstrate that a shift in gamma-amino-butyric acid receptor B (GABA(B)R) 
      function, from inhibitory to excitatory, is required for mTORC1-dependent 
      translation with NMDAR antagonists. Finally, we discuss how GABA(B)R activation 
      of mTORC1 helps resolve key discrepancies between rapid-acting antidepressants 
      and local homeostatic mechanisms.
FAU - Workman, E R
AU  - Workman ER
AD  - U.S. Army Institute of Surgical Research, Burns Injury and Regenerative Medicine, 
      Fort Sam Houston, San Antonio, TX, USA.
FAU - Niere, F
AU  - Niere F
AD  - Department of Physiology and Pharmacology, Wake Forest Health Sciences, 
      Winston-Salem, NC, USA.
FAU - Raab-Graham, K F
AU  - Raab-Graham KF
AD  - Department of Physiology and Pharmacology, Wake Forest Health Sciences, 
      Winston-Salem, NC, USA.
LA  - eng
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, U.S. Gov't, Non-P.H.S.
PT  - Review
DEP - 20171114
PL  - England
TA  - Mol Psychiatry
JT  - Molecular psychiatry
JID - 9607835
RN  - 0 (Antidepressive Agents)
RN  - 0 (GABA Agents)
RN  - 0 (Receptors, GABA)
RN  - 0 (Receptors, N-Methyl-D-Aspartate)
SB  - IM
MH  - Animals
MH  - Antidepressive Agents/therapeutic use
MH  - Depressive Disorder, Major/*pathology/*physiopathology/therapy
MH  - GABA Agents/pharmacology/therapeutic use
MH  - Homeostasis/drug effects/*physiology
MH  - Humans
MH  - Models, Molecular
MH  - Neuronal Plasticity/drug effects/*physiology
MH  - Receptors, GABA/metabolism
MH  - Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors/metabolism
EDAT- 2017/11/15 06:00
MHDA- 2018/12/18 06:00
CRDT- 2017/11/15 06:00
PHST- 2017/06/09 00:00 [received]
PHST- 2017/08/11 00:00 [revised]
PHST- 2017/09/06 00:00 [accepted]
PHST- 2017/11/15 06:00 [pubmed]
PHST- 2018/12/18 06:00 [medline]
PHST- 2017/11/15 06:00 [entrez]
AID - mp2017225 [pii]
AID - 10.1038/mp.2017.225 [doi]
PST - ppublish
SO  - Mol Psychiatry. 2018 Jan;23(1):26-35. doi: 10.1038/mp.2017.225. Epub 2017 Nov 14.