ReviewNeuroactive steroids: molecular mechanisms of action and implications for neuropsychopharmacology
Introduction
Steroid hormone action involves binding of the steroids to their respective intracellular receptors which in turn change their conformation by dissociation from the heat shock proteins, translocate to the nucleus and there bind to the respective response elements which are located in the regulatory regions of target promoters [13], [47], [54]. Thus, steroid hormone receptors act as transcription factors in the regulation of gene expression [13]. In the last decade, considerable evidence has emerged that certain steroids may alter neuronal excitability via their action at the cell surface via interaction with certain neurotransmitter receptors [33], [40], [47]. For steroids with these particular properties the term ‘neuroactive steroids’ has been coined. A variety of neuroactive steroids may be synthesized in the brain itself without the aid of peripheral sources [1], [3]. Such steroids which are formed within the brain from cholesterol are defined also as ‘neurosteroids’ [3]. While the action of steroids at the genome requires a time period from minutes to hours limited by the rate of protein biosynthesis [35], the modulatory effects of neuroactive steroids are fast occurring events within milliseconds to seconds [35]. Thus, the genomic and nongenomic effects of steroids within the central nervous system provide the molecular basis for a broad spectrum of steroid action on neuronal function and plasticity.
Section snippets
Steroid modulation of γ-aminobutyric acid type A (GABAA) receptors
The 3α-reduced metabolites of progesterone and deoxycorticosterone 3α,5α-tetrahydroprogesterone (3α,5α-TH PROG; 3α-hydroxy-5α-pregnan-20-one; allopregnanolone) and 3α,5α-tetrahydrodeoxycorticosterone (3α, 5α-TH DOC; 3α, 21-dihydroxy-5α-pregnan-20-one; allotetrahydrodeoxycorticosterone) were the first steroids that have been shown to modulate neuronal excitability via their interaction with γ-aminobutyric acid type A (GABAA) receptors [33]. GABAA receptors consist of various subunits that form
Genomic effects of neuroactive steroids
In contrast to the classical genomic pathway of steroid hormones [13], the steroids modulating GABAA receptors were initially believed not to regulate gene expression via intracellular steroid receptors because of their inability to bind to such receptors [17], [40]. These steroids may nevertheless affect transcription via progesterone receptors through the generation of metabolites that are ligands for steroid receptors [49]. For example, 3α,5α-TH PROG and 3α,5α-TH DOC may induce transcription
Epilepsy
Drugs that enhance the function of GABAA receptors such as benzodiazepines and barbiturates as well as drugs targeting the GABA bindings site of the GABAA receptor are commonly used as effective antiepileptic agents. Therefore, 3α-reduced neuroactive steroids should also possess anticonvulsant activity. Indeed, these neuroactive steroids exerted pronounced anticonvulsant effects in various animal models [5], [11], [15], [27]. First clinical experiences using progesterone as a precursor molecule
Neuropsychopharmacological perspectives
Neuroactive steroids may modulate neuronal function through their concurrent influence on neuronal excitability and gene expression. This intracellular cross-talk between genomic and non-genomic steroid effects provides the molecular basis for steroid action in the brain and the future development of such compounds in neuropsychopharmacology, both with regard to putative clinical effects and side effects. An important issue is specificity. As yet, no naturally occurring steroid with a really
Acknowledgements
The studies on neuroactive steroids at the Max-Planck-Institute of Psychiatry and the Department of Psychiatry, Ludwig Maximilian University, Munich are supported by the Gerhard Hess Programm of the Deutsche Forschungsgemeinschaft and the German Federal Research Ministry within the promotional emphasis Competence Nets in Medicine.
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2014, Physiology and BehaviorCitation Excerpt :Thus, despite similarities in their actions at GABAA receptors, the effects of neuroactive steroids and benzodiazepines are not identical, suggesting that other mechanisms might be involved in the behavioral effects of neuroactive steroids. While benzodiazepines act exclusively at benzodiazepine sites on GABAA receptors, neuroactive steroids act at distinct modulatory sites on GABAA receptors as well as on other receptors, such as N-methyl-d-aspartate (NMDA) and 5-hydroxytryptamine3 (5-HT3) receptors [8,29], and it might be their actions at these other receptors that account for differences between neuroactive steroids and benzodiazepines. Drug discrimination is a behavioral procedure that has been used to examine the possible differences among positive GABAA modulators, including neuroactive steroids, benzodiazepines and barbiturates.