PMID- 18473173
OWN - NLM
STAT- MEDLINE
DCOM- 20081208
LR  - 20211020
IS  - 1573-6903 (Electronic)
IS  - 0364-3190 (Linking)
VI  - 33
IP  - 10
DP  - 2008 Oct
TI  - Neurosteroid biosynthesis regulates sexually dimorphic fear and aggressive 
      behavior in mice.
PG  - 1990-2007
LID - 10.1007/s11064-008-9718-5 [doi]
AB  - The neurosteroid allopregnanolone is a potent positive allosteric modulator of 
      GABA action at GABA(A) receptors. Allopregnanolone is synthesized in the brain 
      from progesterone by the sequential action of 5alpha-reductase type I (5alpha-RI) 
      and 3alpha-hydroxysteroid dehydrogenase (3alpha-HSD). 5alpha-RI and 3alpha-HSD 
      are co-expressed in cortical, hippocampal, and olfactory bulb glutamatergic 
      neurons and in output neurons of the amygdala, thalamus, cerebellum, and 
      striatum. Neither 5alpha-RI nor 3alpha-HSD mRNAs is expressed in glial cells or 
      in cortical or hippocampal GABAergic interneurons. It is likely that 
      allopregnanolone synthesized in principal output neurons locally modulates 
      GABA(A) receptor function by reaching GABA(A) receptor intracellular sites 
      through lateral membrane diffusion. This review will focus on the behavioral 
      effects of allopregnanolone on mouse models that are related to a sexually 
      dimorphic regulation of brain allopregnanolone biosynthesis. Animal models of 
      psychiatric disorders, including socially isolated male mice or mice that receive 
      a long-term treatment with anabolic androgenic steroids (AAS), show abnormal 
      behaviors such as altered fear responses and aggression. In these animal models, 
      the cortico-limbic mRNA expression of 5alpha-RI is regulated in a sexually 
      dimorphic manner. Hence, in selected glutamatergic pyramidal neurons of the 
      cortex, CA3, and basolateral amygdala and in granular cells of the dentate gyrus, 
      mRNA expression of 5alpha-RI is decreased, which results in a downregulation of 
      allopregnanolone content. In contrast, 5alpha-RI mRNA expression fails to change 
      in the striatum medium spiny neurons and in the reticular thalamic nucleus 
      neurons, which are GABAergic.By manipulating allopregnanolone levels in 
      glutamatergic cortico-limbic neurons in opposite directions to improve [using the 
      potent selective brain steroidogenic stimulant (SBSS) S-norfluoxetine] or induce 
      (using the potent 5alpha-RI inhibitor SKF 105,111) behavioral deficits, 
      respectively, we have established the fundamental role of cortico-limbic 
      allopregnanolone levels in the sexually dimorphic regulation of aggression and 
      fear. By selectively targeting allopregnanolone downregulation in glutamatergic 
      cortico-limbic neurons, i.e., by improving the response of GABA(A) receptors to 
      GABA, new therapeutics would offer appropriate and safe management of psychiatric 
      conditions, including impulsive aggression, irritability, irrational fear, 
      anxiety, posttraumatic stress disorders, and depression.
FAU - Pinna, Graziano
AU  - Pinna G
AD  - Psychiatric Institute, Department of Psychiatry, College of Medicine, University 
      of Illinois at Chicago, 1601W Taylor Street, Chicago, IL 60612, USA. 
      gpinna@psych.uic.edu
FAU - Agis-Balboa, Roberto Carlos
AU  - Agis-Balboa RC
FAU - Pibiri, Fabio
AU  - Pibiri F
FAU - Nelson, Marianela
AU  - Nelson M
FAU - Guidotti, Alessandro
AU  - Guidotti A
FAU - Costa, Erminio
AU  - Costa E
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Review
DEP - 20080513
PL  - United States
TA  - Neurochem Res
JT  - Neurochemical research
JID - 7613461
RN  - 0 (Anabolic Agents)
RN  - 0 (Androstanes)
RN  - 0 (RNA, Messenger)
RN  - 0 (Receptors, GABA-A)
RN  - 0 (SKF 105111)
RN  - 01K63SUP8D (Fluoxetine)
RN  - 4R1VB9P8V3 (Stanozolol)
RN  - 6PG9VR430D (Nandrolone)
RN  - BXO86P3XXW (Pregnanolone)
RN  - EC 1.3.99.5 (3-Oxo-5-alpha-Steroid 4-Dehydrogenase)
RN  - K8D70XE2F4 (norfluoxetine)
RN  - WI93Z9138A (Testosterone Propionate)
SB  - IM
MH  - 3-Oxo-5-alpha-Steroid 4-Dehydrogenase/genetics
MH  - Aggression/drug effects/physiology
MH  - Anabolic Agents/adverse effects
MH  - Androstanes/pharmacology
MH  - Animals
MH  - Behavior, Animal/drug effects/physiology
MH  - Down-Regulation
MH  - Fear/drug effects/physiology
MH  - Female
MH  - Fluoxetine/analogs & derivatives/pharmacology
MH  - Frontal Lobe/drug effects/metabolism
MH  - Male
MH  - Mice
MH  - Muscle, Skeletal/anatomy & histology/drug effects
MH  - Nandrolone/pharmacology
MH  - Organ Size/drug effects
MH  - Pregnanolone/*biosynthesis
MH  - RNA, Messenger/metabolism
MH  - Receptors, GABA-A/drug effects/physiology
MH  - *Social Isolation
MH  - Stanozolol/pharmacology
MH  - Stereotyped Behavior/drug effects
MH  - Synaptic Transmission/drug effects/physiology
MH  - Testosterone Propionate/*pharmacology
RF  - 137
EDAT- 2008/05/14 09:00
MHDA- 2008/12/17 09:00
CRDT- 2008/05/14 09:00
PHST- 2007/12/06 00:00 [received]
PHST- 2008/04/14 00:00 [accepted]
PHST- 2008/05/14 09:00 [pubmed]
PHST- 2008/12/17 09:00 [medline]
PHST- 2008/05/14 09:00 [entrez]
AID - 10.1007/s11064-008-9718-5 [doi]
PST - ppublish
SO  - Neurochem Res. 2008 Oct;33(10):1990-2007. doi: 10.1007/s11064-008-9718-5. Epub 
      2008 May 13.