Selective Antagonism of 5α-Reduced Neurosteroid Effects at GABA<sub>A</sub> Receptors

Mennerick, Steven; He, Yejun; Jiang, Xin; Manion, Brad D.; Wang, Mingde; Shute, Amanda A.; Benz, Ann; Evers, Alex S.; Covey, Douglas F.; Zorumski, Charles F.

doi:10.1124/mol.65.5.1191

Cited by 82 publications

(92 citation statements)

References 18 publications

(21 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…There have been several attempts to use molecular modeling to explain how a similar binding region of GABA A receptors could interact with both 5␣-and 5␤-reduced neurosteroids (Purdy et al, 1990). However, the recent documentation of a synthetic selective antagonist of allopregnanolone's actions at GABA A receptors, which does not block those of pregnanolone, clearly implies that there are different sites of interactions of these two types of neurosteroids with GABA A receptors (Mennerick et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

Characterization of the Discriminative Stimulus Effects of the Neuroactive Steroid Pregnanolone in DBA/2J and C57BL/6J Inbred Mice

Shannon

Porcu

Purdy

et al. 2005

J Pharmacol Exp Ther

View full text Add to dashboard Cite

Neurosteroids represent a class of endogenous compounds that exert rapid, nongenomic effects through neurotransmitter receptor systems such as GABA A . Two neurosteroids, allopregnanolone (3␣-hydroxy-5␣-pregnan-20-one) and pregnanolone (3␣-hydroxy-5␤-pregnan-20-one), possess anxiolytic and sedative properties and show substitution for ethanol, benzodiazepines, and barbiturates in drug discrimination assays. This study aimed to examine the effects of strain and sex on the discriminative stimulus effects of pregnanolone. Twelve male and female DBA/2J mice and 12 male and female C57BL/6J mice were trained to discriminate 10 mg/kg pregnanolone from saline. The male C57BL/6J mice had to be removed from the study due to increased seizures apparently associated with the chronic intermittent pregnanolone administration used in drug discrimination. GABA A -positive modulators, neuroactive steroids, N-methyl-D-aspartate (NMDA) antagonists, and 5-hydroxytryptamine (5-HT) 3 agonists were tested for pregnanolone substitution. In DBA/2J and C57BL/6J mice, a benzodiazepine, barbiturate, and GABAergic neuroactive steroids all substituted for the stimulus effects of pregnanolone. NMDA antagonists, 5-HT 3 agonists, and zolpidem failed to substitute for pregnanolone's discriminative stimulus in either sex or strain. Pentobarbital and midazolam were more potent in producing pregnanolone-like discriminative stimulus effects in DBA/2J mice. Differences in sensitivities to neurosteroids between the two strains were not evident. These results provide a comprehensive look at pregnanolone's discriminative stimulus effects in two commonly used strains of mice. The present data suggest that many of the previously documented neurosteroid-induced behavioral differences between the DBA/2J and C57BL/6J are acute effects and are not apparent in a drug discrimination procedure.Neurosteroids represent a class of endogenous compounds that can act as modulators of many neurotransmitter receptors such as ␥-aminobutyric acid A (GABA A ), N-methyl-Daspartate (NMDA), and 1 receptors. Of particular interest is the interaction of reduced pregnane neurosteroids such as pregnanolone (3␣-hydroxy-5␤-pregnan-20-one), allopregnanolone (3␣-hydroxy-5␣-pregnan-20-one), and 3␣,21-dihydroxy-5␣-pregnan-20-one (alloTHDOC), with the GABA A receptor. These steroids are 10 times more potent than diazepam and flurazepam and 200 times more potent than pentobarbital at potentiating Cl Ϫ flux at the GABA A receptor (Morrow and Paul, 1988). Behavioral evidence also suggests an interaction among the pregnane neurosteroids at the GABA A receptor system. Allopregnanolone, alloTHDOC, and pregnanolone all exhibit anxiolytic, sedative/hypnotic, anticonvulsant, and motor incoordinating behavioral effects . Endogenously, these neurosteroids are involved in the regulation of sleep and response to stressful situations and also in disorders such as epilepsy, premenstrual stress disorder, depression, and drug abuse. Further characterization of the receptor systems involved in th...

show abstract

Section: Discussionmentioning

confidence: 99%

Characterization of the Discriminative Stimulus Effects of the Neuroactive Steroid Pregnanolone in DBA/2J and C57BL/6J Inbred Mice

Shannon

Porcu

Purdy

et al. 2005

J Pharmacol Exp Ther

View full text Add to dashboard Cite

show abstract

“…Fitting of the doseresponse relationships were performed using the Hill equation as described in the legend to Drugs. All drugs were from Sigma (St. Louis, MO), except (3␣,5␣)-17-phenylandrost-16-en-3-ol (17PA), which was synthesized as described (Mennerick et al, 2004). Steroids and 17PA were prepared as stock solutions in DMSO.…”

Section: Methodsmentioning

confidence: 99%

“…17PA has no effect on GABA responses or potentiation of GABA responses by benzodiazepines or barbiturates, but 17PA significantly antagonizes 5␣-reduced steroid effects at GABA A receptors (Mennerick et al, 2004). 17PA antagonizes direct gating more strongly than potentiation (Mennerick et al, 2004), so we tested 17PA against responses to 300 nM 3␣5␣P alone and 300 nM 3␣5␣P used as a potentiator of responses to 0.5 M GABA. Figure 3 shows that in a solitary glutamatergic neuron, responses to 3␣5␣P alone were completely antagonized by 10 M 17PA, but in the same cell, significant potentiation was still detectable in the combined presence of GABA, 3␣5␣P, and 17PA.…”

Section: Direct Gating At Low Steroid Concentrationsmentioning

confidence: 99%

Slow Actions of Neuroactive Steroids at GABA_AReceptors

Shu¹,

Eisenman²,

Jinadasa³

et al. 2004

J. Neurosci.

104

135

View full text Add to dashboard Cite

Neuroactive steroids are potent and efficacious modulators of GABA A receptor activity and are potent sedatives and anesthetics. These positive modulators of GABA A receptors both potentiate the actions of GABA at the receptor and, at higher concentrations, directly gate the channel. The contribution of direct gating to the cellular and behavioral effects of neuroactive steroids is considered of little significance because it has been generally found that concentrations well above those needed for anesthesia are required to gate channels. By studying solitary glutamatergic neurons devoid of synaptic GABA input, we show that direct gating occurs and significantly alters membrane excitability at concentrations Յ100 nM. We propose that the relevance of direct gating has been overlooked partly because of the extremely slow kinetics of receptor activation and deactivation. We show that slow deactivation of directly gated currents does not result from an inherently tight ligand-receptor interaction because the slow deactivation is markedly accelerated by ␥-cyclodextrin application. We hypothesize that steroids access the relevant GABA A receptor site from a non-aqueous reservoir, likely the plasma membrane, and that it is slow reservoir accumulation and departure that accounts for the slow kinetics of receptor gating by neuroactive steroids.

show abstract

“…Neurosteroids possess distinct, characteristic effects on the membrane potential and current conductance mainly via potentiation of GABAA receptors at low doses, and direct activation of receptor chloride channel at higher concentrations. As a results, upon administration neurosteroids exert anxiolytic, analgesic, anticonvulsive, sedative and hypnotic effects, while applied at higher doses may induce a state of general anesthesia [40,[168][169][170][171]. Although the most important effects of neurosteroids are mediated via GABAA receptors, they also exert various effects on an array of ligand-gated ion channels and distinct…”

Section: Effects Of Neurosteroids At Gabaa Receptorsmentioning

confidence: 99%

GABA Receptors: Pharmacological Potential and Pitfalls

Jembrek¹,

Vlainić

2015

CPD

106

View full text Add to dashboard Cite

Gamma-amino butyric acid (GABA), the major inhibitory neurotransmitter in the mammalian central nervous system, plays a key role in the regulation of neuronal transmission throughout the brain, affecting numerous physiological and psychological processes. Changes in GABA levels provoke disbalance between excitatory and inhibitory signals, and are involved in the development of numerous neuropsychiatric disorders. GABA exerts its effects via ionotropic (GABAA) and metabotropic (GABAB) receptors. Both types of receptors are targeted by many clinically important drugs that affect GABAergic function and are widely used in the treatment of anxiety disorder, epilepsy, insomnia, spasticity, aggressive behaviour, and other pathophysiological conditions and diseases. Of particular importance are drugs that modulate GABAA receptor complex, such as benzodiazepines, barbiturates, neuroactive steroids, intravenous and inhalational anesthetics, and ethanol. Molecular interactions and subsequent pharmacological effects induced by drugs acting at GABAA receptors are extremely complex due to structural heterogeneity of GABAA receptors and existence of numerous allosterically interconnected binding sites and various chemically distinct ligands that are able to bound to them. There is a growing interest in the development and application of subtype-selective drugs that will achieve specific therapeutic benefits without undesirable side effects. The aim of this review is to briefly summarize the key pharmacological properties of GABA receptors, and to present selected novel findings with the potential to open new perspectives in the development of more effective therapeutic strategies.

show abstract

Selective Antagonism of 5α-Reduced Neurosteroid Effects at GABA_A Receptors

Cited by 82 publications

References 18 publications

Characterization of the Discriminative Stimulus Effects of the Neuroactive Steroid Pregnanolone in DBA/2J and C57BL/6J Inbred Mice

Characterization of the Discriminative Stimulus Effects of the Neuroactive Steroid Pregnanolone in DBA/2J and C57BL/6J Inbred Mice

Slow Actions of Neuroactive Steroids at GABA_AReceptors

GABA Receptors: Pharmacological Potential and Pitfalls

Contact Info

Product

Resources

About

Selective Antagonism of 5α-Reduced Neurosteroid Effects at GABAA Receptors

Cited by 82 publications

References 18 publications

Characterization of the Discriminative Stimulus Effects of the Neuroactive Steroid Pregnanolone in DBA/2J and C57BL/6J Inbred Mice

Characterization of the Discriminative Stimulus Effects of the Neuroactive Steroid Pregnanolone in DBA/2J and C57BL/6J Inbred Mice

Slow Actions of Neuroactive Steroids at GABAAReceptors

GABA Receptors: Pharmacological Potential and Pitfalls

Contact Info

Product

Resources

About

Selective Antagonism of 5α-Reduced Neurosteroid Effects at GABA_A Receptors

Slow Actions of Neuroactive Steroids at GABA_AReceptors