Allosteric Actions of Central Nervous System Depressants Including Anesthetics on Subtypes of the Inhibitory γ‐Aminobutyric Acid<sub>A</sub> Receptor—Chloride Channel Complex<sup>a</sup>

Olsen, Richard W.; Sapp, Douglas M.; Bureau, M.; Turner, David M.; Kokka, Norio

doi:10.1111/j.1749-6632.1991.tb33838.x

Cited by 55 publications

(26 citation statements)

References 52 publications

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“…Since GABA-active neurosteroids play an important role in the pathogenesis of anxiety and depression [Strohle et al, 1999;Guidotti et al, 2001;Reddy, 2003], it is possible to expect that novel GABAergic steroid agents will be a useful tool in the treatment of steroid-dependent disorders including premenstrual and menopausal syndromes [Barbaccia et al, 2000;Sundstrom et al, 1997;SundstromPoromaa et al, 2003] characterized by increased anxiety and depression. In addition, steroids may play a unique modulatory role in tuning sensitivity of GABAergic receptors to GABA and other GABAactive substances [Turner et al, 1989;Olsen et al, 1991; also see Olsen and Sapp, 1995, for review]. The genomic mechanism of neurosteroid action may include effects of expression of genes encoding subunits of GABAergic receptors [Gulinello et al, 2001].…”

Section: Resultsmentioning

confidence: 98%

Role of GABA in anxiety and depression

2007

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This review assesses the parallel data on the role of gamma-aminobutyric acid (GABA) in depression and anxiety. We review historical and new data from both animal and human experimentation which have helped define the key role for this transmitter in both these mental pathologies. By exploring the overlap in these conditions in terms of GABAergic neurochemistry, neurogenetics, brain circuitry, and pharmacology, we develop a theory that the two conditions are intrinsically interrelated. The role of GABAergic agents in demonstrating this interrelationship and in pointing the way to future research is discussed.

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Section: Resultsmentioning

confidence: 98%

Role of GABA in anxiety and depression

2007

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“…However, many of these positive observations involved high (≥100 mM) doses. One difference between EtOH and general anesthetics was the lack of readily reproducible effect of EtOH on ligand (e.g., GABA, benzodiazepine, or convulsant) binding in vitro, as opposed to anesthetics, where agents that enhance function (Cl − flux or electrophysiology) also modulate binding (Olsen et al, 1991).…”

Section: Evidence For Low Concentration Alcohol Enhancement Of Gaba Amentioning

confidence: 99%

Low dose acute alcohol effects on GABAA receptor subtypes

Wallner

Hanchar

Olsen

2006

Pharmacology & Therapeutics

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GABA A receptors (GABA A Rs) are the main inhibitory neurotransmitter receptors and have long been implicated in mediating at least part of the acute actions of ethanol. For example, ethanol and GABAergic drugs including barbiturates and benzodiazepines share many pharmacological properties. Besides the prototypical synaptic GABA A R subtypes, nonsynaptic GABA A Rs have recently emerged as important regulators of neuronal excitability. While high doses (≥100 mM) of ethanol have been reported to enhance activity of most GABA A R subtypes, most abundant synaptic GABA A Rs are essentially insensitive to ethanol concentrations that occur during social ethanol consumption (<30 mM). However, extrasynaptic δ and β3 subunit-containing GABA A Rs, associated in the brain with α4or α6 subunits, are sensitive to low millimolar ethanol concentrations, as produced by drinking half a glass of wine. Additionally, we found that a mutation in the cerebellar α6 subunit (α6R100Q), initially reported in rats selectively bred for increased alcohol sensitivity, is sufficient to produce increased alcohol-induced motor impairment and further increases of alcohol sensitivity in recombinant α6β3δ receptors. Furthermore, the behavioral alcohol antagonist Ro15-4513 blocks the low dose alcohol enhancement on α4/6/β3δ receptors, without reducing GABA-induced currents. In binding assays α4β3δ GABA A Rs bind [ 3 H] Ro15-4513 with high affinity, and this binding is inhibited, in an apparently competitive fashion, by low ethanol concentrations, as well as analogs of Ro15-4513 that are active to antagonize ethanol or Ro15-4513's block of ethanol. We conclude that most low to moderate dose alcohol effects are mediated by alcohol actions on alcohol/Ro15-4513 binding sites on GABA A R subtypes.

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“…Some barbiturates exhibit convulsant activity in addition to their anesthetic activity [ 1], Recent work indicates that barbiturates may produce anesthesia by specific actions on brain receptors, including receptors for exci tatory amino acids (EAAs) [2][3][4] and y-aminobutyric acid (GABA) [5], EAAs themselves produce convulsion [6] and facilitate kindling [7], while blockers o f EAA receptors can pro duce anesthesia [8] and enhance the anesthe sia produced by volatile and nonvolatile gen eral anesthetics [ …”

Section: Introductionmentioning

confidence: 99%

Effect of Anesthetic and Convulsant Barbiturates on N-Methyl-D-Aspartate Receptor-Mediated Calcium Flux in Brain Membrane Vesicles

Daniell¹

1994

Pharmacology

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The effects of anesthetic and convulsant barbiturates on brain N-methyl-D-aspartate (NMDA) receptor function were examined in a cell-free membrane vesicle preparation from mouse hippocampus. Increases in intracellular free calcium concentrations (Ca_i) were determined using a fluorescent dye, Indo-1 after stimulation with the NMDA receptor agonist, L-glutamate. Anesthetic barbiturates inhibited NMDA responses in a concentration-dependent manner with a rank order of potency of secobarbital > amobarbital > pentobarbital > mephobarbital = Phenobarbital >> barbital. However, the IC50 values for these barbiturates were larger than probable blood anesthetic concentrations. Barbiturates with both anesthetic and convulsant effects in mice [optical isomers of pentobarbital and secobarbital, 5-(2-cyclohexylideneethyl)-5-ethylbarbituric acid and (+/–)-dimethylbutylbarbituric acid] also reduced NMDA responses. Inhibition of NMDA responses by racemic pentobarbital or isomers of pentobarbital was noncompetitive. Resting Cai was altered by all barbiturates tested except secobarbital and barbital, but not in a consistent manner, suggesting that the effect of barbiturates on resting Ca_i is not related either to their effects on NMDA receptor responses or to their behavioral effects. Therse results show that anesthetic and convulsant barbiturates inhibit NMDA responses, but their anesthetic and convulsant activities may be primarily due to their effects on other brain targets.

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Allosteric Actions of Central Nervous System Depressants Including Anesthetics on Subtypes of the Inhibitory γ‐Aminobutyric Acid_A Receptor—Chloride Channel Complex^a

Cited by 55 publications

References 52 publications

Role of GABA in anxiety and depression

Role of GABA in anxiety and depression

Low dose acute alcohol effects on GABAA receptor subtypes

Effect of Anesthetic and Convulsant Barbiturates on N-Methyl-D-Aspartate Receptor-Mediated Calcium Flux in Brain Membrane Vesicles

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Allosteric Actions of Central Nervous System Depressants Including Anesthetics on Subtypes of the Inhibitory γ‐Aminobutyric AcidA Receptor—Chloride Channel Complexa

Cited by 55 publications

References 52 publications

Role of GABA in anxiety and depression

Role of GABA in anxiety and depression

Low dose acute alcohol effects on GABAA receptor subtypes

Effect of Anesthetic and Convulsant Barbiturates on N-Methyl-D-Aspartate Receptor-Mediated Calcium Flux in Brain Membrane Vesicles

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Allosteric Actions of Central Nervous System Depressants Including Anesthetics on Subtypes of the Inhibitory γ‐Aminobutyric Acid_A Receptor—Chloride Channel Complex^a