PMID- 24795582
OWN - NLM
STAT- PubMed-not-MEDLINE
DCOM- 20140505
LR  - 20211021
IS  - 1662-5153 (Print)
IS  - 1662-5153 (Electronic)
IS  - 1662-5153 (Linking)
VI  - 8
DP  - 2014
TI  - Pregnanolone Glutamate, a Novel Use-Dependent NMDA Receptor Inhibitor, Exerts 
      Antidepressant-Like Properties in Animal Models.
PG  - 130
LID - 10.3389/fnbeh.2014.00130 [doi]
LID - 130
AB  - A number of studies demonstrated a rapid onset of an antidepressant effect of 
      non-competitive N-methyl-d-aspartic acid receptor (NMDAR) antagonists. 
      Nonetheless, its therapeutic potential is rather limited, due to a high 
      coincidence of negative side-effects. Therefore, the challenge seems to be in the 
      development of NMDAR antagonists displaying antidepressant properties, and at the 
      same time maintaining regular physiological function of the NMDAR. Previous 
      results demonstrated that naturally occurring neurosteroid 3alpha5beta-pregnanolone 
      sulfate shows pronounced inhibitory action by a use-dependent mechanism on the 
      tonically active NMDAR. The aim of the present experiments is to find out whether 
      the treatment with pregnanolone 3alphaC derivatives affects behavioral response to 
      chronic and acute stress in an animal model of depression. Adult male mice were 
      used throughout the study. Repeated social defeat and forced swimming tests were 
      used as animal models of depression. The effect of the drugs on the 
      locomotor/exploratory activity in the open-field test was also tested together 
      with an effect on anxiety in the elevated plus maze. Results showed that 
      pregnanolone glutamate (PG) did not induce hyperlocomotion, whereas both 
      dizocilpine and ketamine significantly increased spontaneous locomotor activity 
      in the open field. In the elevated plus maze, PG displayed anxiolytic-like 
      properties. In forced swimming, PG prolonged time to the first floating. Acute 
      treatment of PG disinhibited suppressed locomotor activity in the repeatedly 
      defeated group-housed mice. Aggressive behavior of isolated mice was reduced 
      after the chronic 30-day administration of PG. PG showed antidepressant-like and 
      anxiolytic-like properties in the used tests, with minimal side-effects. Since PG 
      combines GABAA receptor potentiation and use-dependent NMDAR inhibition, 
      synthetic derivatives of neuroactive steroids present a promising strategy for 
      the treatment of mood disorders. HIGHLIGHTS: -3alpha5beta-pregnanolone glutamate (PG) is 
      a use-dependent antagonist of NMDA receptors.-We demonstrated that PG did not 
      induce significant hyperlocomotion.-We showed that PG displayed anxiolytic-like 
      and antidepressant-like properties.
FAU - Holubova, Kristina
AU  - Holubova K
AD  - Institute of Physiology, Academy of Sciences of the Czech Republic , Prague , 
      Czech Republic.
FAU - Nekovarova, Tereza
AU  - Nekovarova T
AD  - Institute of Physiology, Academy of Sciences of the Czech Republic , Prague , 
      Czech Republic.
FAU - Pistovcakova, Jana
AU  - Pistovcakova J
AD  - Faculty of Medicine, Department of Pharmacology, Masaryk University , Brno , 
      Czech Republic.
FAU - Sulcova, Alexandra
AU  - Sulcova A
AD  - Central European Institute of Technology, Masaryk University , Brno , Czech 
      Republic.
FAU - Stuchlik, Ales
AU  - Stuchlik A
AD  - Institute of Physiology, Academy of Sciences of the Czech Republic , Prague , 
      Czech Republic.
FAU - Vales, Karel
AU  - Vales K
AD  - Institute of Physiology, Academy of Sciences of the Czech Republic , Prague , 
      Czech Republic.
LA  - eng
PT  - Journal Article
DEP - 20140416
PL  - Switzerland
TA  - Front Behav Neurosci
JT  - Frontiers in behavioral neuroscience
JID - 101477952
PMC - PMC3997017
OTO - NOTNLM
OT  - 3alpha5beta-pregnanolone glutamate
OT  - NMDA channel blocker
OT  - anxiety
OT  - depression
OT  - neuroactive steroid
EDAT- 2014/05/06 06:00
MHDA- 2014/05/06 06:01
PMCR- 2014/01/01
CRDT- 2014/05/06 06:00
PHST- 2013/12/19 00:00 [received]
PHST- 2014/03/29 00:00 [accepted]
PHST- 2014/05/06 06:00 [entrez]
PHST- 2014/05/06 06:00 [pubmed]
PHST- 2014/05/06 06:01 [medline]
PHST- 2014/01/01 00:00 [pmc-release]
AID - 10.3389/fnbeh.2014.00130 [doi]
PST - epublish
SO  - Front Behav Neurosci. 2014 Apr 16;8:130. doi: 10.3389/fnbeh.2014.00130. 
      eCollection 2014.