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Neurosteroids: endogenous regulators of the GABA(A) receptor. Nat Rev Neurosci 6:565-575

Neurosciences Institute, Division of Pathology and Neuroscience, Ninewells Hospital and Medical School, Dundee University, Dundee DD19SY, UK.
Nature reviews Neuroscience (Impact Factor: 31.38). 08/2005; 6(7):565-75. DOI: 10.1038/nrn1703
Source: PubMed

ABSTRACT GABA(A) (gamma-aminobutyric acid type A) receptors mediate most of the 'fast' synaptic inhibition in the mammalian brain and are targeted by many clinically important drugs. Certain naturally occurring pregnane steroids can potently and specifically enhance GABA(A) receptor function in a nongenomic (direct) manner, and consequently have anxiolytic, analgesic, anticonvulsant, sedative, hypnotic and anaesthetic properties. These steroids not only act as remote endocrine messengers, but also can be synthesized in the brain, where they modify neuronal activity locally by modulating GABA(A) receptor function. Such 'neurosteroids' can influence mood and behaviour in various physiological and pathophysiological situations, and might contribute to the behavioural effects of psychoactive drugs.

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    • "5a-reductase inhibition by blocking the metabolism of T and P to its metabolites, could lead to accumulation of precursors and some of them have shown neuroprotective activity in MPTP mice such as estrogens, P and dehydroepiandrosterone (DHEA) (Bourque et al., 2009) (Callier et al., 2001). Given that the P metabolite AP also exhibits protective activity in MPTP mice (Adeosun et al., 2012), neuroprotective effects could be due to activation of P receptor by P and DHP, and also to activation of the g-aminobutyric acid type A (GABA-A) receptor by AP (Belelli and Lambert, 2005). The neuroprotective effects observed here are not likely to be mediated by GABA-A activation by AP since this metabolite is likely decreased due to reduction of P metabolism by 5a-reductase inhibition. "
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    Neuropharmacology 05/2015; 97. DOI:10.1016/j.neuropharm.2015.05.015 · 4.82 Impact Factor
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    • "Neuroactive steroids are molecules acting in the nervous system including steroids produced by the nervous system (i.e., neurosteroids) and hormonal steroids coming from classical steroidogenic tissues (i.e., gonads and adrenal glands) [1]. Several reviews have extensively considered and discussed this topic in the central nervous system (CNS), because the first observations were obtained in the brain [2] [3] [4] [5] [6] [7]. However, more recent results have indicated that the peripheral nervous system (PNS) also synthesizes and metabolizes neuroactive steroids and is a target for these molecules. "
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    • "An additional and partly related explanation could be related to the laminar distribution of steroid-sensitive GABA A R subunits. Indeed, a1, a3 and d subunits are the most sensitive to 3a5a- reduced steroid potentiation (Belelli & Lambert, 2005). Given that a1 is absent from superficial layers (Bohlhalter et al., 1996) and the situation regarding d is still under debate, a3 remains as the most probable steroid-sensitive GABA A R target in the superficial dorsal horn. "
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