PMID- 24997854
OWN - NLM
STAT- MEDLINE
DCOM- 20150602
LR  - 20211021
IS  - 1432-2072 (Electronic)
IS  - 0033-3158 (Print)
IS  - 0033-3158 (Linking)
VI  - 231
IP  - 17
DP  - 2014 Sep
TI  - Pregnenolone sulfate as a modulator of synaptic plasticity.
PG  - 3537-56
LID - 10.1007/s00213-014-3643-x [doi]
AB  - RATIONALE: The neurosteroid pregnenolone sulfate (PregS) acts as a cognitive 
      enhancer and modulator of neurotransmission, yet aligning its pharmacological and 
      physiological effects with reliable measurements of endogenous local 
      concentrations and pharmacological and therapeutic targets has remained elusive 
      for over 20 years. OBJECTIVES: New basic and clinical research concerning 
      neurosteroid modulation of the central nervous system (CNS) function has emerged 
      over the past 5 years, including important data involving pregnenolone and 
      various neurosteroid precursors of PregS that point to a need for a critical 
      status update. RESULTS: Highly specific actions of PregS affecting excitatory 
      N-methyl-D-aspartate receptor (NMDAR)-mediated synaptic transmission and the 
      pharmacological effects of PregS on various receptors and ion channels are 
      discussed. The discovery of a high potency (nanomolar) signal transduction 
      pathway for PregS-induced NMDAR trafficking to the cell surface via a Ca(2+)- and 
      G protein-coupled receptor (GPCR)-dependent mechanism and a potent (EC50 ~ 2 pM) 
      direct enhancement of intracellular Ca(2+) levels is discussed in terms of its 
      agonist effects on long-term potentiation (LTP) and memory. Lastly, preclinical 
      and clinical studies assessing the promnestic effects of PregS and pregnenolone 
      toward cognitive dysfunction in schizophrenia, and altered serum levels in 
      epilepsy and alcohol dependence, are reviewed. CONCLUSIONS: PregS is present in 
      human and rodent brain at physiologically relevant concentrations and meets most 
      of the criteria for an endogenous neurotransmitter/neuromodulator. PregS likely 
      plays a significant role in modulation of glutamatergic excitatory synaptic 
      transmission underlying learning and memory, yet the molecular target(s) for its 
      action awaits identification.
FAU - Smith, Conor C
AU  - Smith CC
AD  - Laboratory of Molecular Neurobiology, Department of Pharmacology & Experimental 
      Therapeutics, Boston University School of Medicine, 72 East Concord St., Boston, 
      MA, 02118, USA.
FAU - Gibbs, Terrell T
AU  - Gibbs TT
FAU - Farb, David H
AU  - Farb DH
LA  - eng
GR  - R01 MH049469/MH/NIMH NIH HHS/United States
GR  - T32 GM008541/GM/NIGMS NIH HHS/United States
GR  - T32GM008541/GM/NIGMS NIH HHS/United States
GR  - R01MH049469/MH/NIMH NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Review
DEP - 20140706
PL  - Germany
TA  - Psychopharmacology (Berl)
JT  - Psychopharmacology
JID - 7608025
RN  - 0 (Neurotransmitter Agents)
RN  - 0 (Nootropic Agents)
RN  - BXO86P3XXW (Pregnanolone)
SB  - IM
MH  - Animals
MH  - Humans
MH  - Neuronal Plasticity/*drug effects
MH  - Neurotransmitter Agents
MH  - Nootropic Agents/pharmacology
MH  - Pregnanolone/*pharmacology/physiology/therapeutic use
MH  - Synapses/*drug effects
PMC - PMC4625978
MID - NIHMS686668
EDAT- 2014/07/07 06:00
MHDA- 2015/06/03 06:00
PMCR- 2015/10/29
CRDT- 2014/07/07 06:00
PHST- 2014/01/16 00:00 [received]
PHST- 2014/05/24 00:00 [accepted]
PHST- 2014/07/07 06:00 [entrez]
PHST- 2014/07/07 06:00 [pubmed]
PHST- 2015/06/03 06:00 [medline]
PHST- 2015/10/29 00:00 [pmc-release]
AID - 10.1007/s00213-014-3643-x [doi]
PST - ppublish
SO  - Psychopharmacology (Berl). 2014 Sep;231(17):3537-56. doi: 
      10.1007/s00213-014-3643-x. Epub 2014 Jul 6.