ReviewThe socially-isolated mouse: a model to study the putative role of allopregnanolone and 5α-dihydroprogesterone in 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
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