Neurosteroid Biosynthesis Regulates Sexually Dimorphic Fear and Aggressive Behavior in Mice

  title={Neurosteroid Biosynthesis Regulates Sexually Dimorphic Fear and Aggressive Behavior in Mice},
  author={Graziano Pinna and Roberto Carlos Ag{\'i}s-Balboa and Fabio Pibiri and Marianela Nelson and Alessandro Guidotti and Erminio Costa},
  journal={Neurochemical Research},
The neurosteroid allopregnanolone is a potent positive allosteric modulator of GABA action at GABAA receptors. Allopregnanolone is synthesized in the brain from progesterone by the sequential action of 5α-reductase type I (5α-RI) and 3α-hydroxysteroid dehydrogenase (3α-HSD). 5α-RI and 3α-HSD are co-expressed in cortical, hippocampal, and olfactory bulb glutamatergic neurons and in output neurons of the amygdala, thalamus, cerebellum, and striatum. Neither 5α-RI nor 3α-HSD mRNAs is expressed in… 

Ganaxolone improves behavioral deficits in a mouse model of post-traumatic stress disorder

Ganaxolone at non-sedating concentrations appears to improve dysfunctional emotional behavior associated with deficits in ALLO in mice and may provide a therapeutic GABAergic alternative to SSRIs for the treatment of PTSD or other disorders in which ALLO biosynthesis may be impaired.

Anabolic Androgenic Steroid Abuse: Multiple Mechanisms of Regulation of GABAergic Synapses in Neuroendocrine Control Regions of the Rodent Forebrain

How exposure to AAS alters GABAergic transmission and neural activity within these forebrain regions is reviewed, taking advantage of in vitro systems and both wild‐type and genetically altered mouse strains to better understand how these synthetic steroids affect the neural systems that underlie the regulation of reproduction and the expression of sexual behaviours.

Multifunctional aspects of allopregnanolone in stress and related disorders

  • Anjana BaliA. Jaggi
  • Biology, Medicine
    Progress in Neuro-Psychopharmacology and Biological Psychiatry
  • 2014

Corticotropin-Releasing Factor Modulation of Forebrain GABAergic Transmission has a Pivotal Role in the Expression of Anabolic Steroid-Induced Anxiety in the Female Mouse

It is demonstrated that chronic, but not acute, exposure of female mice during adolescence to AAS augments anxiety-like behaviors; effects that were blocked by central infusion of the CRF receptor type 1 antagonist, antalarmin.

Neurosteroids Reduce Social Isolation-Induced Behavioral Deficits: A Proposed Link with Neurosteroid-Mediated Upregulation of BDNF Expression

The hypothesis that in PTSD or depressed patients, brain allopregnanolone levels, and BDNF expression upregulation may be mechanisms at least partially involved in the beneficial actions of antidepressants or other selective brain steroidogenic stimulant molecules is addressed.

The pregnane xenobiotic receptor, a prominent liver factor, has actions in the midbrain for neurosteroid synthesis and behavioral/neural plasticity of female rats

PXR may be an upstream factor of TSPO for neurosteroidogenesis of 3α,5α-THP in the VTA for lordosis, independent of peripheral glands, and substantiates future studies investigating factors known for their prominent actions in the peripheral organs for modulating brain function and its augmentation.

Regulation of Neurosteroid Biosynthesis by Neurotransmitters and Neuropeptides

It has been found that glutamate, acting through kainate and/or AMPA receptors, rapidly inactivates P450arom, and that melatonin production by the pineal gland and eye inhibits the biosynthesis of 7α-hydroxypregnenolone, while prolactin produced by the adenohypophysis enhances the formation of 7 α-OH-Δ5P.



Down-regulation of neurosteroid biosynthesis in corticolimbic circuits mediates social isolation-induced behavior in mice

In male mice, the expression of 5α-RI mRNA, which is the rate-limiting-step enzyme of ALLO biosynthesis, is specifically down-regulated in glutamatergic pyramidal neurons that converge on the amygdala from cortical and hippocampal regions.

Characterization of brain neurons that express enzymes mediating neurosteroid biosynthesis

It is demonstrated that 5α-R type I and 3α-HSD colocalize in cortical, hippocampal, and olfactory bulb glutamatergic principal neurons and in some output neurons of the amygdala and thalamus, and data suggest that ALLO and THDOC modulate GABA action at GABAA receptors, either with an autocrine or a paracrine mechanism or by reaching GabAA receptor intracellular sites through lateral membrane diffusion.

Neurosteroidogenesis: relevance to neurosteroid actions in brain and modulation by psychotropic drugs.

  • M. Barbaccia
  • Biology, Medicine
    Critical reviews in neurobiology
  • 2004
Brain neurosteroid concentrations show not only a brain region, but also a cell-specific expression that may spatially and temporally determine the local concentrations of specific neurosteroids, either produced ex novo or through metabolism of steroid precursors that reach the brain through blood.

Brain 5α-dihydroprogesterone and allopregnanolone synthesis in a mouse model of protracted social isolation

Protracted social isolation in mice may provide a model to investigate whether 5α-DHP by a genomic action, and ALLO by a nongenomic mechanism down-regulate the action of drugs acting as agonist, partial agonists, or positive allosteric modulators of the benzodiazepine recognition sites expressed by GABAA receptors.

Neurosteroids regulate mouse aggression induced by anabolic androgenic steroids

Administration of allopregnanolone or the potent selective brain steroidogenic stimulant S-norfluoxetine, in doses that fail to inhibit 5-hydroxytryptamine reuptake, normalizes olfactory bulb neurosteroid level downregulation and abolishes aggression.

Changes in brain testosterone and allopregnanolone biosynthesis elicit aggressive behavior.

The results support the view that TP-induced aggressive behavior is the result of a TP-mediated neurosteroid biosynthesis down-regulation that can be reversed by the S-NFLX-induced increase of brain Allo content.

Selective serotonin reuptake inhibitors directly alter activity of neurosteroidogenic enzymes.

  • L. D. GriffinS. Mellon
  • Biology, Medicine
    Proceedings of the National Academy of Sciences of the United States of America
  • 1999
The neurosteroid 3alpha-hydroxysteroid-5alpha-pregnan-20-one (allopregnanolone) acts as a positive allosteric modulator of gamma-aminobutyric acid at gamma-aminobutyric acid type A receptors and

Steroids, neuroactive steroids and neurosteroids in psychopathology

  • B. Dubrovsky
  • Biology, Medicine
    Progress in Neuro-Psychopharmacology and Biological Psychiatry
  • 2005