Neurosteroid allopregnanolone inhibits glutamate release from rat cerebrocortical nerve terminals (original) (raw)
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European Neuropsychopharmacology, 2007
The dorsal raphe nucleus (DRN) is the origin of much of the 5-HT innervation of the forebrain. The activity of DRN 5-HT neurons is regulated by a number of receptors including GABA A and 5-HT 1A inhibitory receptors and by excitatory α 1-adrenoceptors. Using in vitro electrophysiological recording we investigated the action of progesterone and its metabolite, allopregnanolone on receptor-mediated responses of DRN 5-HT neurons. Neither allopregnanolone nor progesterone affected the α 1-adrenoceptor agonist-induced firing. Allopregnanolone also had no effect on the inhibitory response to 5-HT. However, allopregnanolone significantly potentiated the inhibitory responses to GABA A receptor agonists. Progesterone did not enhance GABA A receptor-meditated inhibitory responses. Thus, the neuroactive metabolite of progesterone, allopregnanolone, has the ability to cause potentiation of GABA Amediated inhibition of DRN 5-HT neurons. This effect on 5-HT neurotransmission may have relevance for mood disorders commonly associated with reproductive hormone events, such as premenstrual dysphoric disorder and postpartum depression.
Brain Research, 1987
In this study, the neuromodulatory effects of progesterone were tested in an intact neuronal circuit of a model extrahypothalamic CNS area. Spontaneous discharge and responses of single cerebellar Purkinje neurons to microiontophoretically applied ),-aminobutyric acid (GABA) and glutamate were monitored before, during and after either systemic injection, at physiologic doses, or local application of the steroid. By both means of administration, progesterone significantly enhanced inhibitory responses of Purkinje cells to GABA and suppressed glutamate excitation within 3-10 rain post-steroid. These results are consistent with the anxiolytic actions of the steroid.
Acta Physiologica Scandinavica, 2000
The progesterone metabolites allopregnanolone (Allo, 3a-hydroxy-5a-pregnan-20-one) and pregnanolone (Preg, 3a-hydroxy-5b-pregnan-20-one) enhance the c-aminobutyric acid (GABA) action through a distinct site on the GABA A -receptor. Their 3b-isomers epiallopregnanolone (Epiallo, 3bhydroxy-5a-pregnan-20-one) and epipregnanolone (Epipreg, 3b-hydroxy-5b-pregnan-20-one), do not have these effects on GABA A -receptors. We have studied the interaction between Allo/Preg and their 3b-isomers on action potentials in rat hippocampal slices in vitro. The Schaffer collaterals were stimulated electrically in CA1 striatum radiatum and the population spike (POPSP) was recorded in stratum pyramidale. A 0.5-nL droplet of drug was applied locally onto stratum oriens±pyramidale via a pressure pipett. Muscimol (Mus) (12.5 fmol), Allo and Preg (6.25 fmol) caused a reversible inhibition of POPSP. On the other hand, 6.25 fmol Epiallo had no signi®cant effect on POPSP compared with the vehicle control. Combined Epiallo and Allo application caused a dose-dependent reduction of the Allo inhibition of POPSP. A full blockage was seen at a molar ratio of 1:1. Epiallo also blocked the Preg inhibition of POPSP, when the two drugs were combined in a molar ratio of 1:1. Epiallo did not block the Mus inhibition of POPSP, when the two drugs were combined at a molar ratio of 1:2. Bath perfusion of 12.5 lM Epiallo blocked the inhibition of 6.25 fmol Allo on POPSP, but not the inhibition caused by 12.5 fmol Mus. Epipreg did not block the inhibition of Allo and Preg on POPSP, when it was combined with the two latter drugs at a molar ratio of 1:1. Our data suggest that the steroid modulation of the GABA A transmitted inhibition of the CA1 pyramidal neurones is selectively and dose dependently blocked by Epiallo, the 3b-hydroxy-isomer of Allo, but not by Epipreg, the 3bhydroxy-isomer of Preg.
Medroxyprogesterone acetate exacerbates glutamate excitotoxicity
Gynecological Endocrinology, 2006
We previously demonstrated that progesterone functions as a neuroprotective agent whereas medroxyprogesterone acetate (MPA; Provera 1) does not. Moreover, MPA antagonized the neuroprotective and neurotrophic outcomes induced by 17b-estradiol (E 2). Towards developing effective hormone therapies for protection against neurodegeneration, we sought to determine whether formulation, chemical features or prevention versus treatment mode of exposure affected the outcome of MPA treatment in survival of primary hippocampal neurons. Results of these analyses indicated that both crystalline MPA and a pharmaceutical formulation (Depo-Provera 1) lacked neuroprotective efficacy, indicating that the effects were not dependent upon MPA formulation. Likewise, MPA in the prevention and treatment paradigms were equally ineffective at promoting neuronal survival, indicating that timing of MPA administration was not a factor. Further, the detrimental effects of MPA were not due to the presence of the acetate group, as medroxyprogesterone was as ineffective as MPA in promoting neuronal survival. Moreover, MPA pretreatment exacerbated neuron death induced by glutamate excitotoxicity as indicated by a 40% increase in neuron death determined by direct live/dead cell count and a commensurate increase in the number of positive cells by terminal deoxynucleotidyl transferase-mediated nick end-labeling. Collectively these results predict that the progestin formulation of hormone therapy will affect the vulnerability of the central nervous system to degenerative insults.
Journal of Cellular Physiology, 2012
Recent evidence shows that neurotransmitters (e.g., GABA, Ach, adenosine, glutamate) are active on Schwann cells, which form myelin sheaths in the peripheral nervous system under different pathophysiologic conditions. Glutamate, the most important excitatory neurotransmitter, has been recently involved in peripheral neuropathies, thus prevention of its toxic effect is desirable to preserve the integrity of peripheral nervous system and Schwann cells physiology. Removal of glutamate from the extracellular space is accomplished by the high affinity glutamate transporters, so we address our studies to analyze their functional presence in Schwann cells. We first demonstrate that Schwann cells express the EAAC1 transporter in the plasma membrane and in intracellular vesicular compartments of the endocytic recycling pathways. Uptake experiments confirm its presence and functional activity in Schwann cells. Secondly, we demonstrate that the EAAC1 activity can be modulated by exposure to the neurosteroid allopregnanolone 10 nM (a progesterone metabolite proved to support Schwann cells). Transporter up-regulation by allopregnanolone is rapid, does not involve protein neo-synthesis and is prevented by actin depolymerization. Allopregnanolone modulation involves GABA-A receptor and PKC activation, promotes the exocytosis of the EAAC1 transporter from intracellular stores to the Schwann cell membrane, in actin-rich cell tips, and modifies the morphology of cell processes. Finally, we provide evidence that glutamate transporters control the allopregnanolone-mediated effects on cell proliferation. Our findings are the first to demonstrate the presence of a functional glutamate uptake system, which can be dynamically modulated by allopregnanolone in Schwann cells. Glutamate transporters may represent a potential therapeutic target to control Schwann cell physiology.
Tolerance and antagonism to allopregnanolone effects in the rat CNS
2006
Many studies have suggested a relationship between sex steroids and negative mental and mood changes in women. Allopregnanolone, a potent endogenous ligand of the GABA-A receptor and a metabolite of progesterone, is one of the most accused neuroactive steroids. Variations in the levels of neuroactive steroids that influence the activity of the GABA-A receptor cause a vulnerability to mental and emotional pathology. In women, there are physiological conditions in which allopregnanolone production increases acutely (e.g. stress) or chronically (e.g. menstrual cycle, pregnancy), thus exposing the GABA-A receptor to high allopregnanolone concentrations. In such conditions, tolerance to allopregnanolone probably develops. We have evaluated the 3β-hydroxy pregnane steroid UC1011 as a functional antagonist to allopregnanolone-induced negative effects in rats. In vivo, we used the Morris Water Maze (MWM) test of learning and, in vitro, we studied chloride ion uptake into cortical and hippocampal membrane preparations. The steroid UC1011 reduces the allopregnanolone-induced learning impairment in the MWM and the increase in chloride ion uptake induced by allopregnanolone. To detect whether chronic tolerance develops to an allopregnanolone-induced condition, male rats were pretreated with allopregnanolone injections for three or seven days. These rats were then tested in the Morris Water Maze for five days and compared with relevant controls. Rats with seven days' allopregnanolone pretreatment experienced improved performance compared with the acutely allopregnanolone-exposed group, reflecting chronic tolerance development. To study the GABA-A receptor changes in acute allopregnanolone tolerance, we used the silent second (SS) anaesthesia threshold method. At acute tolerance, 90 minutes of anaesthesia, the abundance of the GABA-A receptor α 4 subunit and the expression of the α 4 subunit mRNA in the thalamus ventral-posteriomedial (VPM) nucleus were reduced. There was also a significant negative correlation between the increase in the allopregnanolone dose needed to maintain anaesthesia and the α 4 mRNA in the VPM nucleus. We also investigated whether allopregnanolone tolerance was still present one or two days after the end of the anaesthesia-induced acute tolerance. Tolerance persisted to one day, but not two days, after the treatment and the α 4 subunit mRNA expression in the VPM nucleus was negatively related to the allopregnanolone doses needed after one day. In conclusion, the current thesis shows that the substance UC1011 can reduce the allopregnanolone-induced negative effects in the water maze test. Chronic allopregnanolone tolerance can develop to the effects of allopregnanolone. Allopregnanolone tolerance persists one day after the induction of acute allopregnanolone tolerance. The GABA-A receptor α4 subunit in the thalamus might be involved in the development and persistence of acute tolerance to allopregnanolone.
Neurosteroid modulation of allopregnanolone and GABA effect on the GABA-A receptor
Neuroscience, 2006
The neurosteroid allopregnanolone (ALLO) or 3␣-OH-5␣-pregnane-20-one interacts with the GABA type A receptor chloride ion channel complex and enhances the effect of GABA. Animal and human studies suggest that ALLO plays an important role in several disorders including premenstrual syndrome, anxiety, and memory impairment. In contrast to ALLO, steroids with a hydroxy group in the 3 position usually exert a reducing effect and have recently attracted interest due to their suggested role in counteracting the negative action of ALLO. In this study, five different 3steroids were tested for their ability to modulate GABA-mediated chloride ion uptake in the absence and presence of ALLO in rat brain microsacs preparations. In addition, the effects of the 3-steroids and their interaction with ALLO were investigated by patch-clamp recordings of spontaneous inhibitory postsynaptic currents (sIPSCs) in rat hypothalamic neurons from the medial preoptic nucleus (MPN). All tested 3-steroids reduced the ALLO-enhanced GABA response in cerebral cortex, in hippocampus and in MPN. In cerebellum, only one had this effect. However, in the absence of ALLO, two of the 3-steroids potentiated GABA-evoked chloride ion uptake and prolonged the sIPSCs decay time, whereas the others had little or no effect. Therefore, it is possible that at least some 3-steroids can act as positive GABA A receptor modulators as well as negative modulators depending on whether or not ALLO is present. Finally, these results suggest that the 3-steroids could be of interest as pharmacological agents that could counteract the negative effects of ALLO.
The Neurosteroid Allopregnanolone Modulates Specific Functions in Central and Peripheral Glial Cells
Frontiers in Endocrinology, 2011
Since the first observations on the existence of "neurosteroids" in the 1980s, our understanding of the importance of these endogenous steroids in the control of the central and peripheral nervous system (PNS) has increased progressively. Although most of the observations were made in neuronal cells, equally important are the effects that neurosteroids exert on glial cells. Among the different classes of neurosteroids acting on glial cells, the progesterone 5α-3α metabolite, allopregnanolone, displays a particular mechanism of action involving primarily the modulation of classic GABA receptors. In this review, we focus our attention on allopregnanolone because its effects on the physiology of glial cells of the central and PNS are intriguing and could potentially lead to the development of new strategies for neuroprotection and/or regeneration of injured nervous tissues.
AJP: Cell Physiology, 2013
Rett syndrome (RTT) is a neurodevelopmental disorder with symptoms starting 6–18 mo after birth, while what underlies the delayed onset is unclear. Allopregnanolone (Allop) is a metabolite of progesterone and a potent modulator of GABAA-ergic currents whose defects are seen in RTT. Allop changes its concentration during the perinatal period, which may affect central neurons via the GABAA-ergic synaptic transmission, contributing to the onset of the disease. To determine whether Mecp2 disruption affects Allop modulation, we performed studies in brain slices obtained from wild-type (WT) and Mecp2 −/Y mice. Allop dose dependently suppressed locus coeruleus (LC) neuronal excitability in WT mice, while Mecp2-null neurons showed significant defects. Using optogenetic approaches, channelrhodopsin was specifically expressed in GABA-ergic neurons in which optical stimulation evoked action potentials. In LC neurons of WT mice, Allop exposure increased the amplitude of GABAA-ergic inhibitory p...