Neuroactive steroids and inhibitory neurotransmission: Mechanisms of action and physiological relevance

Belelli, Delia; Herd, Murray B.; Mitchell, Elizabeth A.; Peden, Dianne R.; Vardy, A. E.; Gentet, Luc J.; Lambert, Jeremy J.

doi:10.1016/j.neuroscience.2005.07.021

Cited by 149 publications

(109 citation statements)

References 79 publications

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“…57 Neurosteroid action is brain region and neuron-specific, and neurons of the central nucleus of the amygdala appear relatively insensitive to allopregnanolone. 58 This heterogeneity in neurosteroid sensitivity could be mediated by regional differences in receptor subunit composition, phosphorylation and steroid metabolism. 58 Specifically, allopregnanolone inhibits the a4b2d GABA A receptor, which reduces tonic inhibition and thereby increases excitability.…”

Section: Discussionmentioning

confidence: 99%

“…58 This heterogeneity in neurosteroid sensitivity could be mediated by regional differences in receptor subunit composition, phosphorylation and steroid metabolism. 58 Specifically, allopregnanolone inhibits the a4b2d GABA A receptor, which reduces tonic inhibition and thereby increases excitability. Because this receptor is highly sensitive to neurosteroids, inhibition of this receptor at relatively low neurosteroid concentrations can induce paradoxical effects, 59 and may contribute to amygdala disinhibition.…”

Section: Discussionmentioning

confidence: 99%

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Progesterone selectively increases amygdala reactivity in women

et al. 2007

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The acute neural effects of progesterone are mediated by its neuroactive metabolites allopregnanolone and pregnanolone. These neurosteroids potentiate the inhibitory actions of c-aminobutyric acid (GABA). Progesterone is known to produce anxiolytic effects in animals, but recent animal studies suggest that pregnanolone increases anxiety after a period of low allopregnanolone concentration. This effect is potentially mediated by the amygdala and related to the negative mood symptoms in humans that are observed during increased allopregnanolone levels. Therefore, we investigated with functional magnetic resonance imaging (MRI) whether a single progesterone administration to healthy young women in their follicular phase modulates the amygdala response to salient, biologically relevant stimuli. The progesterone administration increased the plasma concentrations of progesterone and allopregnanolone to levels that are reached during the luteal phase and early pregnancy. The imaging results show that progesterone selectively increased amygdala reactivity. Furthermore, functional connectivity analyses indicate that progesterone modulated functional coupling of the amygdala with distant brain regions. These results reveal a neural mechanism by which progesterone may mediate adverse effects on anxiety and mood.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Progesterone selectively increases amygdala reactivity in women

et al. 2007

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“…Interestingly, some lipid messengers do not require G-protein-coupled receptors to exert their function. For example, neurosteroids interact with membrane GABA-gated receptor channels to enhance neuronal inhibition 75 , whereas oleoylethanolamide and its analogue palmitoylethanolamide engage peroxisome proliferator-activated receptors-α in the cell cytosol and nucleus to regulate feeding 76 and pain 77,78 (fIG. 5).…”

Section: Neurosteroidmentioning

confidence: 99%

A neuroscientist's guide to lipidomics

2007

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| Nerve cells mould the lipid fabric of their membranes to ease vesicle fusion, regulate ion fluxes and create specialized microenvironments that contribute to cellular communication. The chemical diversity of membrane lipids controls protein traffic, facilitates recognition between cells and leads to the production of hundreds of molecules that carry information both within and across cells. With so many roles, it is no wonder that lipids make up half of the human brain in dry weight. The objective of neural lipidomics is to understand how these molecules work together; this difficult task will greatly benefit from technical advances that might enable the testing of emerging hypotheses.

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“…These positive modulators also slow the rate of recovery from desensitization, thus prolonging deactivation since receptors can transit from high-affinity, bound desensitized states to open states at times after GABA has been cleared from the synaptic cleft (for review, Jones and Westbrook, 1996;Vicini, 2004). At concentrations higher than 100nM, positive neurosteroids can directly gate the GABA A receptor (for review, Belelli et al, 2006), although such actions are unlikely to have physiological effects except, perhaps, during pregnancy when neurosteroids are reported to reach such levels (see Section 4). A-ring reduction at the 3 position, as well as a D-ring C 20 or C 17 keto group, are believed to be critical for positive neurosteroid binding (for review, Lambert et al, 1995) (Figure 1).…”

Section: Mechanisms Of Steroid Modulation Of Gaba a Receptorsmentioning

confidence: 99%

“…Specifically, results from recombinant GABA A receptors demonstrate that α subunit composition has a modest, albeit significant, effect on potency and no effect on efficacy for the positive A-ring reduced derivatives at recombinant α x β 1 γ 2L receptors. Substitution of different β subunit isoforms is without effect (for review, Belelli and Lambert, 2005;Belelli et al, 2006). With respect to α subunit composition, α 6 -containing recombinant receptors show the greatest sensitivity to modulation by positive neurosteroids, and those containing α 1 or α 3 subunits are slightly more sensitive than those containing α 2 or α 4 (for review Belelli et al, 2002).…”

Section: Neurosteroidsmentioning

confidence: 99%

Steroid modulation of GABAA receptor-mediated transmission in the hypothalamus: Effects on reproductive function

Henderson

2007

Neuropharmacology

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The hypothalamus, the seat of neuroendocrine control, is exquisitely sensitive to gonadal steroids. For decades it has been known that androgens, estrogens and progestins, acting through nuclear hormone receptors, elicit both organizational and activational effects in the hypothalamus and basal forebrain that are essential for reproductive function. While changes in gene expression mediated by these classical hormone pathways are paramount in governing both sexual differentiation and the neural control of reproduction, it is also clear that steroids impart critical control of neuroendocrine functions through nongenomic mechanisms. Specifically, endogenous neurosteroid derivatives of deoxycorticosterone, progesterone and testosterone, as well and synthetic anabolic androgenic steroids that are self-administered as drugs of abuse, elicit acute effects via allosteric modulation of γ-aminobutyric acid type A receptors. GABAergic transmission within the hypothalamus and basal forebrain is a key regulator of pubertal onset, the expression of sexual behaviors, pregnancy and parturition. Summarized here are the known actions of steroid modulators on GABAergic transmission within the hypothalamus/basal forebrain, with a focus on the medial preoptic area and the supraoptic/paraventricular nuclei that are known to be central players in the control of reproduction.

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Neuroactive steroids and inhibitory neurotransmission: Mechanisms of action and physiological relevance

Cited by 149 publications

References 79 publications

Progesterone selectively increases amygdala reactivity in women

Progesterone selectively increases amygdala reactivity in women

A neuroscientist's guide to lipidomics

Steroid modulation of GABAA receptor-mediated transmission in the hypothalamus: Effects on reproductive function

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