Neuroactive steroids in affective disorders: target for novel antidepressant or anxiolytic drugs?
ABSTRACT In the past decades considerable evidence has emerged that so-called neuroactive steroids do not only act as transcriptional factors in the regulation of gene expression but may also alter neuronal excitability through interactions with specific neurotransmitter receptors such as the GABA(A) receptor. In particular, 3α-reduced neuroactive steroids such as allopregnanolone or allotetrahydrodeoxycorticosterone have been shown to act as positive allosteric modulators of the GABA(A) receptor and to play an important role in the pathophysiology of depression and anxiety. During depression, the concentrations of 3α,5α-tetrahydroprogesterone and 3α,5β-tetrahydroprogesterone are decreased, while the levels of 3β,5α-tetrahydroprogesterone, a stereoisomer of 3α,5α-tetrahydroprogesterone, which may act as an antagonist for GABAergic steroids, are increased. Antidepressant drugs such as selective serotonin reuptake inhibitors (SSRIs) or mirtazapine apparently have an impact on key enzymes of neurosteroidogenesis and have been shown to normalize the disequilibrium of neuroactive steroids in depression by increasing 3α-reduced pregnane steroids and decreasing 3β,5α-tetrahydroprogesterone. Moreover, 3α-reduced neuroactive steroids have been demonstrated to possess antidepressant- and anxiolytic-like effects both in animal and human studies for themselves. In addition, the translacator protein (18 kDa) (TSPO), previously called peripheral benzodiazepine receptor, is the key element of the mitochondrial import machinery supplying the substrate cholesterol to the first steroidogenic enzyme (P450scc), which transforms cholesterol into pregnenolone, the precursor of all neurosteroids. TSPO ligands increase neurosteroidogenesis and are a target of novel anxiolytic drugs producing anxiolytic effects without causing the side effects normally associated with conventional benzodiazepines such as sedation or tolerance. This article is part of a Special Issue entitled: Neuroactive Steroids: Focus on Human Brain.
Chapter: Neurosteroid Biosynthesis Upregulation: A Novel Promising Therapy for Anxiety Disorders and PTSD08/2011; , ISBN: 978-953-307-592-1
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ABSTRACT: Research has elucidated causal links between stress exposure and the development of anxiety disorders, but due to the limited use of female or sex-comparative animal models, little is known about the mechanisms underlying sex differences in those disorders. This is despite an overwhelming wealth of evidence from the clinical literature that the prevalence of anxiety disorders is about twice as high in women compared to men, in addition to gender differences in severity and treatment efficacy. We here review human gender differences in generalized anxiety disorder, panic disorder, posttraumatic stress disorder and anxiety-relevant biological functions, discuss the limitations of classic conflict anxiety tests to measure naturally occurring sex differences in anxiety-like behaviors, describe sex-dependent manifestation of anxiety states after gestational, neonatal, or adolescent stressors, and present animal models of chronic anxiety states induced by acute or chronic stressors during adulthood. Potential mechanisms underlying sex differences in stress-related anxiety states include emerging evidence supporting the existence of two anatomically and functionally distinct serotonergic circuits that are related to the modulation of conflict anxiety and panic-like anxiety, respectively. We discuss how these serotonergic circuits may be controlled by reproductive steroid hormone-dependent modulation of crfr1 and crfr2 expression in the midbrain dorsal raphe nucleus and by estrous stage-dependent alterations of γ-aminobutyric acid (GABAergic) neurotransmission in the periaqueductal gray, ultimately leading to sex differences in emotional behavior.Pflügers Archiv - European Journal of Physiology 04/2013; · 4.46 Impact Factor
06/2011; , ISBN: 978-953-307-592-1del