A Presynaptic Action of the Neurosteroid Pregnenolone Sulfate on GABAergic Synaptic Transmission

Mtchedlishvili, Zakaria

doi:10.1124/mol.64.4.857

Cited by 87 publications

(58 citation statements)

References 40 publications

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“…This neurosteroid enhancement of mIPSCs from medial preoptic neurons has been confirmed by Uchida et al (2002). Sulfated neuroactive steroids can inhibit GABA release from hippocampal pyramidal cells by acting on a sigma receptor (Mtchedlishvili and Kapur, 2003). While our laboratory has confirmed the ability of a sulfated neurosteroid to inhibit GABA release (unpublished data from Purkinje neurons), our laboratory and others (Cooper et al, 1999;Puia et al, 2003) have not observed a change in frequency of mIPSCs at low concentrations of unsulfated neuroactive steroids from terminals influencing hippocampal or cerebellar Purkinje neurons.…”

Section: Neurosteroid Involvement In the Gabamimetic Profile Of Ethansupporting

confidence: 64%

“…As with GABA transmission, a number of presynaptic mechanisms can influence glutamate release (see Brown et al, 2004;Jones and Wonnacott, 2004). Since ethanol increases neurosteroids, another aspect that should receive future attention is the possibility that pregnenolone sulfate may enhance spontaneous glutamate release (see Meyer et al, 2002), while reducing release of GABA (Mtchedlishvili and Kapur, 2003). Such an action would likely relate to adaptations induced by chronic ethanol exposure.…”

Section: Ethanol On Excitatory Drivementioning

confidence: 99%

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A Conceptualization of Integrated Actions of Ethanol Contributing to its GABAmimetic Profile: A Commentary

Criswell

Breese

2005

Neuropsychopharmacol

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Early behavioral investigations supported the contention that systemic ethanol displays a GABAmimetic profile. Microinjection of GABA agonists into brain and in vivo electrophysiological studies implicated a regionally specific action of ethanol on GABA function. While selectivity of ethanol to enhance the effect of GABA was initially attributed an effect on type-1-benzodiazepine (BZD)-GABA A receptors, a lack of ethanol's effect on GABA responsiveness from isolated neurons with this receptor subtype discounted this contention. Nonetheless, subsequent work identified GABA A receptor subtypes, with limited distribution in brain, sensitive to enhancement of GABA at relevant ethanol concentrations. In view of these data, it is hypothesized that the GABAmimetic profile for ethanol is due to activation of mechanisms associated with GABA function, distinct from a direct action on the majority of postsynaptic GABA A receptors. The primary action proposed to account for ethanol's regional specificity on GABA transmission is its ability to release GABA from some, but not all, presynaptic GABAergic terminals. As systemic administration of ethanol increases neuroactive steroids, which can enhance GABA responsiveness, this elevated level of neurosteroids is proposed to magnify the effect of GABA released by ethanol. Additional factors contributing to the degree to which ethanol interacts with GABA function include an involvement of GABA B and other receptors that influence ethanol-induced GABA release, an effect of phosphorylation on GABA responsiveness, and a regional reduction of glutamatergic tone. Thus, an integration of these consequences induced by ethanol is proposed to provide a logical basis for its in vivo GABAmimetic profile.

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Section: Neurosteroid Involvement In the Gabamimetic Profile Of Ethansupporting

confidence: 64%

Section: Ethanol On Excitatory Drivementioning

confidence: 99%

A Conceptualization of Integrated Actions of Ethanol Contributing to its GABAmimetic Profile: A Commentary

Criswell

Breese

2005

Neuropsychopharmacol

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“…Previous studies in chick spinal chord neurons had suggested that PS had a higher potency at GABA A receptors than at NMDA receptors. In the past, we have characterized the PS modulation of GABA A receptors on hippocampal dentate granule cells (Mtchedlishvili et al, 2001) and in cultured hippocampal neurons (Mtchedlishvili and Kapur, 2003) but we have not investigated PS modulation of NMDA currents.…”

Section: Ps Enhancement Of Nmda Receptor Currentsmentioning

confidence: 99%

“…These studies suggest that PS inhibits GABAergic synaptic transmission with greater potency and efficacy than it enhances glutamatergic neurotransmission. PS effects on GABAergic synapses were characterized in detail recently (Mtchedlishvili and Kapur, 2003). PS blocks GABA release in a very potent manner, with an IC 50 of 26 nM, and GABA release is suppressed 80-90% by 1-10 µM PS.…”

Section: Mechanism Of Convulsant Actionmentioning

confidence: 99%

Characterization of the convulsant action of pregnenolone sulfate

Williamson

Mtchedlishvili

2004

Neuropharmacology

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Pregnenolone sulfate (PS) is an endogenous neurosteroid synthesized by glial cells, which acts as a potent convulsant when injected intracerebroventricularly and intraperitoneally. PS is found in relatively high concentrations in the hippocampus. But its convulsant action in the hippocampus has not been characterized. A range of PS doses were infused directly into the right hippocampus of 42 rats, which were subsequently monitored for behavioral and electrographic seizures. At the highest dose (4 µmol), PS produced status epilepticus (SE) and severe behavioral convulsions. As the dose of PS was reduced, the fraction of rats having SE diminished (ED 50 for SE = 2.7 µmol). At doses lower than 300 nmol, PS infusion produced discrete electrographic seizures (ED 50 = 68 nmol) associated with mild behavioral seizures. Both the behavioral seizure score (BSS) and the total number of seizures during the observation period changed in a dose-dependant manner. In separate experiments in cultured hippocampal neurons, PS enhanced NMDA-evoked whole-cell currents (EC 50 = 16 µM). The results demonstrate that the hippocampus is highly sensitive to the convulsant effects of PS and that the enhancement of NMDA currents could contribute to the convulsant action of PS.

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“…PREG-S-is an excitatory neuroactive steroid that inhibits GABA release at nanomolar concentrations (Mtchedlishvili and Kapur, 2003), inhibits GABA A receptors, and potentiates N-methyl-D-aspartate (NMDA) receptor-mediated excitatory responses at micromolar concentrations (Majewska et al, 1988;Wu et al, 1991). PREG-S modulates learning and memory in rodents (Flood et al, 1992;; its concentrations decrease with age and administration of PREG-S reverses cognitive deficits in aged rats (Vallee et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

Differential hypothalamic–pituitary–adrenal activation of the neuroactive steroids pregnenolone sulfate and deoxycorticosterone in healthy controls and alcohol-dependent subjects

Porcu

O'Buckley

Morrow

et al. 2008

Psychoneuroendocrinology

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SummaryEthanol and the neuroactive steroids have interactive neuropharmacological effects and chronic ethanol administration blunts the ethanol-induced increase in neuroactive steroid levels in rodent plasma and brain. Few studies have explored neuroactive steroid regulation in alcohol-dependent human subjects. In fact, the regulation of adrenal neuroactive steroids has not been well defined in healthy controls. We thus explored the regulation of two neuroactive steroids, pregnenolone sulfate (PREG-S) and deoxycorticosterone, by pharmacological challenges to the hypothalamic-pituitaryadrenal (HPA) axis in healthy controls and one-month abstinent alcohol-dependent patients with cooccurring nicotine dependence. Plasma levels of PREG-S and deoxycorticosterone were measured by radioimmunoassay in controls and alcohol-dependent patients after challenges of naloxone, ovine corticotrophin releasing hormone (oCRH), dexamethasone, cosyntropin, and cosyntropin following high-dose dexamethasone. In addition, basal diurnal measures of both hormones were obtained. PREG-S plasma levels in healthy controls were increased by cosyntropin challenge (with and without dexamethasone pretreatment) and decreased by dexamethasone challenge. However, PREG-S concentrations were not altered by naloxone or oCRH challenges, suggesting that PREG-S is not solely regulated by hypothalamic or pituitary stimulation. Deoxycorticosterone, in contrast, is regulated by HPA challenge stimulation in a manner similar to cortisol. Alcohol-dependent patients had a blunted PREG-S response to cosyntropin (with and without dexamethasone pretreatment). Furthermore, the time to peak deoxycorticosterone response following oCRH was delayed in alcoholdependent patients compared to controls. These results indicate that plasma PREG-S and deoxycorticosterone levels are differentially regulated by HPA axis modulation in human plasma. Further, alcohol-dependent patients show a blunted PREG-S response to adrenal stimulation and a delayed deoxycorticosterone response to oCRH challenge.

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A Presynaptic Action of the Neurosteroid Pregnenolone Sulfate on GABAergic Synaptic Transmission

Cited by 87 publications

References 40 publications

A Conceptualization of Integrated Actions of Ethanol Contributing to its GABAmimetic Profile: A Commentary

A Conceptualization of Integrated Actions of Ethanol Contributing to its GABAmimetic Profile: A Commentary

Characterization of the convulsant action of pregnenolone sulfate

Differential hypothalamic–pituitary–adrenal activation of the neuroactive steroids pregnenolone sulfate and deoxycorticosterone in healthy controls and alcohol-dependent subjects

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