Facilitatory action of etomidate and pentobarbital on recurrent inhibition in rat hippocampal pyramidal neurons

Proctor, WR; Mynlieff, Michelle; Dunwiddie, Thomas V.

doi:10.1523/jneurosci.06-11-03161.1986

Cited by 55 publications

(14 citation statements)

References 34 publications

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“…Etomidate is well recognized to directly enhance the activity of GABA A receptors (Ashton and Wauquier, 1985; Proctor et al, 1986; Belelli et al, 1997; Hill-Venning et al, 1997; Rüsch et al, 2004.). Agents that positively modulate GABA A receptors have been found to confer robust protection in the 6-Hz seizure test (Kaminski et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

11β-Hydroxylase inhibitors protect against seizures in mice by increasing endogenous neurosteroid synthesis

Kamiński

Rogawski

2011

Neuropharmacology

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Steroid 11β-hydroxylase (CYP11B1; EC 1.14.15.4) is a mitochondrial enzyme located in the zona fasciculata of the adrenal cortex and also in the brain that mediates the conversion of 11-deoxycortisol to cortisol and 11-deoxycorticosterone (DOC) to corticosterone. Inhibitors of CYP11B1, such as metyrapone and etomidate, reduce glucocorticoid synthesis and raise levels of DOC providing greater availability for metabolic conversion to the GABAA receptor modulating neurosteroid allotetrahydrodeoxycorticosterone (THDOC). Because THDOC is a potent anticonvulsant, it is plausible that CYP11B1 inhibitors could protect against seizures. Here we demonstrate that metyrapone affords dose-dependent protection against 6-Hz seizures 30 min after injection (ED50, 191 mg/kg), but is markedly more potent at 6 h (ED50, 30 mg/kg). Similarly, etomidate is also protective at 30 min and 6 h (ED50 values, 4.5 and 1.7 mg/kg). Finasteride, an inhibitor of neurosteroid synthesis, attenuated the anticonvulsant effects of both CYP11B1 inhibitors at 6 h, but not 30 min following their injection. Plasma THDOC levels measured by liquid chromatography-mass spectrometry were markedly increased 6 h after injection of both CYP11B1 inhibitors and this increase was attenuated by finasteride pretreatment. We conclude that inhibition of CYP11B1 causes delayed seizure protection due to slow build-up of neurosteroids. Early seizure protection is independent of neurosteroids.

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Section: Discussionmentioning

confidence: 99%

11β-Hydroxylase inhibitors protect against seizures in mice by increasing endogenous neurosteroid synthesis

Kamiński

Rogawski

2011

Neuropharmacology

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“…To block FFW inhibition elicited by current spread to excitatory inputs in stratum oriens, a cut was made which extended through stratum oriens, stratum pyramidale, and stratum radiatum (leaving approximately the outer 2/3 of the alveus), at a location between the alvear stimulation electrode and the recording electrode ( Fig. 4 A and see Proctor et al, 1986). Stimulus intensity, in each paradigm, was set to evoke a control population spike between 1 and 3 mV.…”

Section: Methodsmentioning

confidence: 99%

Differential effects of mu‐ and delta‐receptor selective opioid agonists on feedforward and feedback GABAergic inhibition in hippocampal brain slices

Lupica

Dunwiddie

1991

Synapse

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Previous studies have suggested that opioid receptor activation in the hippocampus increases pyramidal neuron excitability by reducing GABAergic inhibition. This hypothesis has received support with regard to mu-receptor agonists but has not been adequately tested with selective delta-receptor agonists. In the present investigation we compared the effects of the selective mu-opioid receptor agonist [Tyr-(D-Ala)-Gly-(N-Me-Phe)-Gly-ol]-enkephalin (DAGO) and the delta-receptor agonist [D-Pen2,D-Pen5]-enkephalin (DPDPE) to those of bicuculline methiodide (BMI) on extracellularly recorded feedforward (FFW) and recurrent (feedback; FB) inhibition. It was discovered that the control population spike response, evoked by Schaffer collateral/commissural axon stimulation, increased in response to DAGO, DPDPE, and BMI, while the secondary or test response increased only in the presence of DAGO and BMI. The resulting hypothesis that delta-opioid receptor activation facilitates synaptically evoked responses independently of a reduction of inhibition was investigated by examining the effect of DPDPE on the field EPSP response recorded in stratum radiatum of CA1, or postsynaptically on a burst response activated through antidromic stimulation of pyramidal neurons in low calcium medium. delta-Opioid receptor activation had no effect on either the field EPSP response or the burst response, suggesting that neither synaptic transmission nor postsynaptic excitability were augmented. Finally, the possibility that DPDPE acts to enhance pyramidal cell excitability independently of GABAergic transmission was further investigated by examining responses to both mu- and delta-opioid agonists following treatment with BMI (30 microM). Responses to DPDPE and DAGO were completely blocked by this treatment, supporting the involvement of a GABAergic circuit in the actions of these enkephalins. These results suggest that the delta-opioid receptor agonist DPDPE may mediate a reduction in GABAergic inhibition which is not detectable using paired stimulation techniques designed to examine FFW and FB inhibition in the hippocampal slice.

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“…show GABAA-mimetic properties (2)(3)(4)(5)(6). If these observations of specific 'GABA modulatory properties can be extended to other general anesthetics with diverse chemical structures, a case for a possible unitary mechanism for general anesthesia involving specific modulation of GABA-mediated neuronal inhibition will be strengthened.…”

mentioning

confidence: 97%

Volatile anesthetics gate a chloride current in postnatal rat hippocampal neurons

1992

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A volatile anesthetic-gated current was characterized in patch-clamped cultured postnatal rat hippocampal neurons. In this preparation, the major volatile anesthetics, isoflurane, halothane, and enflurane, open an anion-selective conductance. This volatile anesthetic-gated current exhibits anion selectivity with a chloride-to-acetate permeability ratio of 15, shows outward rectification well described by the constant field equation, and is activated in a dose-dependent fashion with half-maximal response to isoflurane at 0.8 mM (0.032 atm). The current persists in the absence of external Ca2+ and is not blocked by strychnine, a glycine antagonist. However, the gamma-aminobutyric acidA (GABAA) antagonists, bicuculline and picrotoxinin, and the nonspecific anion channel blocker, 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS), completely block the response. These observations suggest that volatile anesthetics, like several other general anesthetics such as barbiturates, steroids, and etomidate, have a GABA-mimetic effect on vertebrate central neurons in culture. It is not clear whether this GABAA-gating property is a prerequisite for all general anesthetics. However, under normal physiological conditions of low intracellular Cl-, it is likely that drugs with both direct GABA agonist and GABA modulatory properties will produce overall depression of the central nervous system by increasing the normal inhibitory synaptic influence and by directly hyperpolarizing neurons.

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Facilitatory action of etomidate and pentobarbital on recurrent inhibition in rat hippocampal pyramidal neurons

Cited by 55 publications

References 34 publications

11β-Hydroxylase inhibitors protect against seizures in mice by increasing endogenous neurosteroid synthesis

11β-Hydroxylase inhibitors protect against seizures in mice by increasing endogenous neurosteroid synthesis

Differential effects of mu‐ and delta‐receptor selective opioid agonists on feedforward and feedback GABAergic inhibition in hippocampal brain slices

Volatile anesthetics gate a chloride current in postnatal rat hippocampal neurons

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