Neurosteroid biosynthesis regulates sexually dimorphic fear and aggressive behavior in mice.
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.
Pinna
Graziano
G
Psychiatric Institute, Department of Psychiatry, College of Medicine, University of Illinois at Chicago, 1601W Taylor Street, Chicago, IL 60612, USA. gpinna@psych.uic.edu
Agis-Balboa
Roberto Carlos
RC
Pibiri
Fabio
F
Nelson
Marianela
M
Guidotti
Alessandro
A
Costa
Erminio
E
D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase / Q000235:genetics; D000374:Aggression / Q000187:drug effects / Q000502:physiology; D045930:Anabolic Agents / Q000009:adverse effects; D000731:Androstanes / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D015536:Down-Regulation; D005239:Fear / Q000187:drug effects / Q000502:physiology; D005260:Female; D005473:Fluoxetine / Q000031:analogs & derivatives / Q000494:pharmacology; D005625:Frontal Lobe / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D018482:Muscle, Skeletal / Q000033:anatomy & histology / Q000187:drug effects; D009277:Nandrolone / Q000494:pharmacology; D009929:Organ Size / Q000187:drug effects; D011280:Pregnanolone / Q000096:biosynthesis*; D012333:RNA, Messenger / Q000378:metabolism; D011963:Receptors, GABA-A / Q000187:drug effects / Q000502:physiology; D012934:Social Isolation; D013197:Stanozolol / Q000494:pharmacology; D013239:Stereotyped Behavior / Q000187:drug effects; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology; D043343:Testosterone Propionate / Q000494:pharmacology*
D045930:Anabolic Agents; D000731:Androstanes; D012333:RNA, Messenger; D011963:Receptors, GABA-A; C473295:SKF 105111; D005473:Fluoxetine; D013197:Stanozolol; D009277:Nandrolone; D011280:Pregnanolone; D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase; C036139:norfluoxetine; D043343:Testosterone Propionate