Elsevier

Brain Research Reviews

Volume 37, Issues 1–3, November 2001, Pages 110-115
Brain Research Reviews

Review
The socially-isolated mouse: a model to study the putative role of allopregnanolone and 5α-dihydroprogesterone in psychiatric disorders

https://doi.org/10.1016/S0165-0173(01)00129-1Get rights and content

Abstract

Allopregnanolone (3α,5α-TH PROG) and 5α-dihydroprogesterone (5α-DH PROG), the two most important neuroactive steroids synthesized in the brain, potently modulate neuronal activity by allosterically regulating GABA action at GABAA receptors or by changing specific GABAA receptor subunit gene expression, respectively. We recently reported [Proc. Natl. Acad. Sci. USA 95 (1998) 3239] that in patients with severe depression there is a decrease in the CSF levels of 3α,5α-TH PROG, which is normalized by treatment with drugs (i.e. fluoxetine) that improve psychopathology. The mechanism by which fluoxetine and other selective serotonin reuptake inhibitors normalize 3α,5α-TH PROG CSF levels appears to involve a direct stimulation of 3α-hydroxysteroidoxidoreductase (3α-HSD), an enzyme that catalyses the reduction of 5α-DH PROG into 3α,5α-TH PROG. Here, we propose the use of socially-isolated mice that have a downregulation of 3α,5α-TH PROG and of 5α-DH PROG expression to establish a model to study the behavioral consequences of this deficiency. After 4–6 weeks of isolation, these mice exhibit increased anxiety and aggressive behavior and also a decreased response to the administration of GABA-mimetic drugs. In these mice, the decrease in 3α,5α-TH PROG is selectively normalized by the use of fluoxetine in doses that reduce behavioral abnormalities. In addition, the expression of 5α-reductase Type I mRNA and protein was lower in socially-isolated mice than that in group-housed mice whereas 3α-HSD mRNA expression remained unchanged. The results of these studies may enable us to design drugs that specifically affect neurosteroidogenic enzymatic activities and may provide an efficacious treatment for the psychopathologies associated with psychiatric disorders.

Section snippets

Neurosteroid biosynthesis

Neurosteroidogenesis begins with the conversion of cholesterol (CHOL) to pregnenolone (PREG) by the cytochrome P450 side-chain cleavage (scc) enzyme located in the inner mitochondrial membrane of glial cells [1], [2], [7], [11], [18].

Studies originating in our laboratory have documented the existence of an autocrine brain system that regulates PREG biosynthesis via a glial mitochondrial receptor termed mitochondrial benzodiazepine receptor (MBR) because it binds peripheral benzodiazepine

Genomic and non-genomic actions of neurosteroids

Extensive evidence indicates the high potency and efficacy of the neurosteroid 3α,5α-TH PROG on the modulation of the action of GABA at GABAA receptors (for a review, see Refs. [7], [12], [19]).

In contrast to the classic steroid hormones that have a well-defined genomic effect acting at intracellular receptors, 3α,5α-TH PROG, and congeners (5β stereoisomers, THDOC) that modulate GABAA receptor function are not believed to regulate gene expression via intracellular steroid receptors because of

Physiological role of 3α,5α-TH PROG in the regulation of GABAA receptor function

The relationship between 3α,5α-TH PROG and GABAA receptor function has been based on the pharmacological actions of exogenously administered 3α,5α-TH PROG or its congeners. However, such evidence neither allows nor is it sufficient to conclude that endogenously produced 3α,5α-TH PROG plays a role in the physiological regulation of brain GABAergic tone or in abnormal behaviors associated with the downregulation of GABAergic transmission that we suspect are operative in various psychiatric

Is there a role for 3α,5α-TH PROG downregulation in the symptoms of unipolar depression?

In a recent study, we demonstrated that the improvement of unipolar depression symptoms (Hamilton score) elicited by fluoxetine treatment lasting 8–10 weeks was correlated with a normalization of endogenous CSF 3α,5α-TH PROG content, which was significantly decreased prior to fluoxetine treatment [28]. An independent group has now confirmed the concept that 3α,5α-TH PROG can be decreased in depressed patients and that fluoxetine normalizes 3α,5α-TH PROG in these patients [24]. These data allow

An animal model to study the role of 3α,5α TH PROG and 5α-DH PROG downregulation in the psychopathologies associated with various psychiatric disorders

To test the hypothesis that some of the actions of mood stabilizers, tranquilizers, or antidepressant drugs that ameliorate the symptoms associated with depression, anxiety, posttraumatic stress disorders, obsessive-compulsive disorders, and premenstrual dysphoria exert their beneficial effects via normalization of downregulated brain levels of 3α,5α-TH PROG or 5α-DH PROG, we turned our attention to a mouse model involving protracted long-term adaptation to the stress of social isolation, in

References (28)

  • E.E. Baulieu et al.

    Synthesis and functions of neurosteroids

  • D.L. Cheney et al.

    Gas chromatographic mass fragmentographic quantitation of 3alpha-hydroxysteroid 5alpha-pregnan-20-one (allopregnanolone) and its precursors in blood and brain of adrenalectomized and castrated rats

    J. Neurosci.

    (1995)
  • D.L. Cheney et al.

    Pregnenolone sulfate antagonizes dizocilpine amnesia: role for allopregnanolone

    Neuroreport

    (1995)
  • A. Concas et al.

    Role of brain allopregnanolone in the plasticity of gamma-aminobutyric acid type A receptor in rat brain during pregnancy and after delivery

    Proc. Natl. Acad. Sci. USA

    (1998)
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