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Critical Reviews™ in Neurobiology

ISSN for PRINT: 0892-0915

Institutional price:	$649.00
Issues per year:	4

Best Paper Award Selection - Editorial Board Site

2004, Volume16

194 pages

DOI: 10.1615/CritRevNeurobiol.v16.i12

Issue price - $252.00

Neurosteroidogenesis: Relevance to Neurosteroid Actions in Brain and Modulation by Psychotropic Drugs

Maria Luisa Barbaccia
Department of Neuroscience, Section of Pharmacology, University of Rome "Tor Vergata" Schoool of Medicine, Via Montpellier, 1, 00133-Rome, Italy

ABSTRACT

Neurosteroids—i.e., steroid produced in brain ex novo or through metabolism of precursors—affect neuronal and brain functions through genomic and nongenomic mechanisms, depending on their molecular structure. Among neurosteroids, 3α-hydroxylated, 5α-reduced metabolites of progesterone (3α-hydroxy,5α-pregnan-20one/3α,5α-THP) and deoxycorticosterone (3α,21-dihydroxy,5α-pregnan-20one/3α,5α-THDOC) are positive allosteric modulators of γ-aminobutyric acid (GABA) action at GABA_A receptors. In rodents, a reduction of their endogenous brain concentrations rapidly lowers the potency of GABA in eliciting GABA_A receptor-mediated inhibitory postsynaptic currents. This effect is related to anxiety-like behavior, increased aggression, and a reduced sensitivity to the loss of righting reflex induced by GABA_A receptor agonist or positive modulators. Conversely, enhancement of 3α,5α-THP or 3α,5α-THDOC brain content results in anxiolysis, sedation/hypnosis, anticonvulsant, and anesthetic action. Different classes of psychotropic drugs—i.e., antidepressants, selected atypical antipsychotics, ethanol, γ-hydroxybutyric acid—increase neurosteroid concentrations in brain, and these increases may be relevant to their pharmacological actions. Drug-induced increases of neurosteroids in rodent brain are often associated with elevation of their plasma content, such that alterations of plasma steroid concentrations are assumed to reflect parallel changes in brain. Nevertheless, brain neurosteroid concentrations are uneven across various regions, and the dose-dependence of their response to a pharmacological challenge shows brain-regional differences as well. These observations are consistent with the present knowledge on the distribution of steroidogenic enzymes in brain—they 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.