Neurosteroids: Biosynthesis and Function of These Novel Neuromodulators

Compagnone, Nathalie A.; Mellon, Synthia H.

doi:10.1006/frne.1999.0188

Cited by 768 publications

(588 citation statements)

References 232 publications

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“…Peripheral benzodiazepine receptors (PBRs) enhance the transport of cholesterol from the outer to the inner mitochondrial membrane forming pregnenolone, which is subsequently metabolized to P 4 and 3α5α-THP [31]. This de novo synthesis of pregnenolone in the midbrain VTA occurs independent of peripheral gland secretion and in response to reproductively-relevant stimuli.…”

Section: P 4 'S Actions In the Vta For Lordosismentioning

confidence: 99%

Membrane actions of progestins at dopamine type 1-like and GABAA receptors involve downstream signal transduction pathways

Frye

Walf

2008

Steroids

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In the ventral tegmental area (VTA), progestins facilitate lordosis via rapid actions at membrane dopamine Type 1-like (D 1 ) and/or GABA A receptors (GBRs), rather than via cognate, intracellular progestin receptors. Downstream signal transduction pathways involved in these effects were investigated using lordosis as a bioassay. If progestins' actions at D 1 and/or GBRs in the VTA require activation of G-proteins, adenylyl cyclase, cyclic AMP-dependent protein kinase A (PKA), phospholipase C (PLC), and/or PKC, then pharmacologically blocking these pathways would be expected to attenuate progestin-facilitated lordosis and its enhancement by D 1 and GBR activity. Ovariectomized, estradiol-primed rats were infused first with vehicle or signal transduction inhibitor, and second with vehicle, a D 1 or GBR agonist, and then with vehicle or progestins to the VTA. Rats were tested for lordosis following infusions. Results indicated that initiation of G-proteins, adenylyl cyclase, PKA, PLC, or PKC in the VTA is required for rapid effects of progestins through D 1 and/ or GBRs to facilitate lordosis. As well, progestins' actions at n-methyl-d-aspartate receptors (NMDARs) may modulate activity at D 1 and/or GBRs and mitogen activated protein kinase may be a common signaling pathway. Findings from a microarray study demonstrated that there was upregulation of genes associated with steroid metabolism, GBRs, D 1 , NMDARs and signal transduction factors in the midbrain VTA of naturally-receptive mated compared to non-mated rats. Thus, in the VTA, progestins have rapid membrane-mediated actions via D 1 , GBRs, NMDARs and their downstream signal transduction pathways.

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Section: P 4 'S Actions In the Vta For Lordosismentioning

confidence: 99%

Membrane actions of progestins at dopamine type 1-like and GABAA receptors involve downstream signal transduction pathways

Frye

Walf

2008

Steroids

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“…Neurosteroids can be metabolized in the CNS from plasma-derived steroids or directly synthesized in the brain (for review, Baulieu 1998; Compagnone and Mellon, 2000). A-ring reduced neurosteroids, such as allopregnanolone (3α-hydroxy-5α-pregnan-20-one), THDOC (5α-pregnane-3α,21-diol-20-one) and 3α-diol (5α-androstane-3α,17β-diol) are positive allosteric modulators of the GABA A receptor that augment channel burst durations by increasing the opening frequency (and therefore the relative proportion of long duration single channel events) without concomitant changes in the open duration time constants themselves (for review, Henderson and Jorge, 2004).…”

Section: Mechanisms Of Steroid Modulation Of Gaba a Receptorsmentioning

confidence: 99%

“…Naturally occurring neurosteroids are synthesized from cholesterol in both peripheral organs and in the central nervous system (CNS), primarily by glial cells, and can be classified as positive (enhancing) or negative (blocking) allosteric modulators of the GABA A receptor (for review, Baulieu, 1998;Compagnone and Mellon, 2000;Belelli and Lambert, 2005). Synthetic steroids, including anesthetics such as alphaxalone and ganaxolone (for review, Belelli and Lambert, 2005) and the anabolic androgenic steroids (AAS) (for review, Clark et al, 2004;2006) also act as allosteric modulators of the GABA A receptor.…”

Section: Introductionmentioning

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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“…Similarly, interactions of corticosterone with other ligand gated ion channels, such as the nicotinic or serotonin-3 receptors, have not been speci®cally examined. In contrast to cortisol or corticosterone, steroid hormones that possess a 5a-reduced A-ring (such as metabolites of progesterone) are known to affect ligand gated ion channel function in a rapid and reversible manner (45,46). These actions, however, do not involve nuclear receptors but membrane recognition sites to which these steroid metabolites bind with a relatively low af®nity.…”

Section: Corticosteroid Effects On Ligand Gated Ion Channelsmentioning

confidence: 99%

Corticosteroid Actions in the Hippocampus

Joëls

2001

J Neuroendocrinology

181

111

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Corticosteroid hormones can enter the brain and bind to two intracellular receptor types that regulate transcription of responsive genes: (i) the high af®nity mineralocorticoid receptors and (ii) the glucocorticoid receptors with approximately 10-fold lower af®nity. Although most cells in the brain predominantly express glucocorticoid receptors, principal cells in limbic structures such as the hippocampus often contain glucocorticoid as well as mineralocorticoid receptors. Recent electrophysiological studies have examined the consequences of transcriptional regulation via the two receptor types for information transfer in the hippocampus. It was found that, under resting conditions, corticosteroids do not markedly alter electrical activity. However, if neurones are shifted towards more depolarized or hyperpolarized potentials due to the action of neurotransmitters, slow and adaptive effects of the corticosteroid hormones become apparent. In general, mineralocorticoid receptor occupation maintains steady electrical activity in hippocampal neurones. Brief activation of glucocorticoid receptors leads to increased in¯ux of calcium, which normally helps to slowly reverse temporarily raised electrical activity. These slow and persistent corticosteroid actions will alter network function within the hippocampus, thus contributing to behavioural adaptation in response to stress. Modulation of hippocampal activity by corticosteroids also affects hippocampal output (e.g. to inhibitory interneurones which control hypothalamic-pituitary-adrenal axis activity). The enhanced calcium in¯ux after glucocorticoid receptor activation can become a risk factor when cells are simultaneously exposed to strong depolarizing inputs, such as those occuring during ischaemia. Similarly, chronically elevated corticosteroid levels (or lack of corticosteroids) could endanger hippocampal cell function. The latter may contribute to the precipitation of clinical symptoms in diseases associated with chronically aberrant corticosteroid levels.

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Neurosteroids: Biosynthesis and Function of These Novel Neuromodulators

Cited by 768 publications

References 232 publications

Membrane actions of progestins at dopamine type 1-like and GABAA receptors involve downstream signal transduction pathways

Membrane actions of progestins at dopamine type 1-like and GABAA receptors involve downstream signal transduction pathways

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

Corticosteroid Actions in the Hippocampus

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