Low‐Level Hyperbaric Antagonism of Ethanol‐Induced Locomotor Depression in C57BL/6J Mice: Dose Response

Bejanian, Marina; Jones, Brenda L.; Alkana, Ronald L.

doi:10.1111/j.1530-0277.1993.tb05644.x

Cited by 15 publications

(18 citation statements)

References 27 publications

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“…This work used pressures up to 12 ATA heliox to antagonize behavioral and biochemical effects of ethanol (Alkana and Malcolm 1981; Alkana et al . 1992; Bejanian et al . 1993; Davies and Alkana 1998, 2001; Davies et al .…”

Section: Discussionmentioning

confidence: 99%

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Multiple sites of ethanol action in α1 and α2 glycine receptors suggested by sensitivity to pressure antagonism

Davies

Crawford

Trudell

et al. 2004

Journal of Neurochemistry

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The current study used an ethanol antagonist, increased atmospheric pressure, to test the hypothesis that ethanol acts on multiple sites in glycine receptors (GlyRs). The effects of 12 times normal atmospheric pressure of helium-oxygen gas (pressure) on ethanol-induced potentiation of GlyR function in Xenopus oocytes expressing human a1, a2 or the mutant a1(A52S) GlyRs were measured using two-electrode voltage clamp. Pressure reversibly antagonized potentiation of glycine in a1 GlyR by 40-200 mM ethanol, but did not antagonize 10 and 25 mM ethanol in the same oocytes. In contrast, pressure did not significantly affect potentiation of glycine by 25-100 mM ethanol in a2 GlyRs, nor did pressure alter ethanol response in the A52S mutant. Pressure did not affect baseline receptor function or response to glycine in the absence of ethanol. These findings provide the first direct evidence for multiple sites of ethanol action in GlyRs. The sites can be differentiated on the basis of ethanol concentration, subunit and structural composition and sensitivities to pressure antagonism of ethanol. Parallel studies with butanol support this conclusion. The mutant a1(A52S) GlyR findings suggest that increased attention should be focused on the amino terminus as a potential target for ethanol action.

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Section: Discussionmentioning

confidence: 99%

“…1999). The antagonism occurred without measurable changes in baseline behavior, CNS or receptor excitability (Bejanian et al . 1993; Davies et al .…”

Section: Discussionmentioning

confidence: 99%

Multiple sites of ethanol action in α1 and α2 glycine receptors suggested by sensitivity to pressure antagonism

Davies

Crawford

Trudell

et al. 2004

Journal of Neurochemistry

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“…Further studies of the involvement of the GlyR EC domain in ethanol action have taken advantage of the pharmacological phenomenon that increased atmospheric pressure (pressure) acts as a direct mechanistic antagonist to ethanol. Pressures up to 12 times normal antagonized the behavioral and biochemical actions of ethanol (Alkana and Malcolm, 1981; Alkana et al, 1992; Bejanian et al, 1993; Davies and Alkana, 1998, 2001) without altering ethanol pharmacokinetics, behavioral or electrophysiological baselines, or CNS excitation (Davies et al, 1994, 1999; Syapin et al, 1996). Thus, if a GlyR site is involved in ethanol modulation, mutating it should alter the effects of pressure as well as ethanol.…”

Section: Glycine Receptors: Defining Alcohol Binding Through Mutagenementioning

confidence: 99%

Alcohol-Binding Sites in Distinct Brain Proteins: The Quest for Atomic Level Resolution

Howard

Slesinger

Davies

et al. 2011

Alcoholism: Clinical and Experimental Research

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Defining the sites of action of ethanol on brain proteins is a major prerequisite to understanding the molecular pharmacology of this drug. The main barrier to reaching an atomic-level understanding of alcohol action is the low potency of alcohols, ethanol in particular, which is a reflection of transient, low-affinity interactions with their targets. These mechanisms are difficult or impossible to study with traditional techniques such as radioligand binding or spectroscopy. However, there has been considerable recent progress in combining X-ray crystallography, structural modeling, and site-directed mutagenesis to define the sites and mechanisms of action of ethanol and related alcohols on key brain proteins. We review such insights for several diverse classes of proteins including inwardly rectifying potassium, transient receptor potential, and neurotransmit-ter-gated ion channels, as well as protein kinase C epsilon. Some common themes are beginning to emerge from these proteins, including hydrogen bonding of the hydroxyl group and van der Waals interactions of the methylene groups of ethanol with specific amino acid residues. The resulting binding energy is proposed to facilitate or stabilize low-energy state transitions in the bound proteins, allowing ethanol to act as a “molecular lubricant” for protein function. We discuss evidence for characteristic, discrete alcohol-binding sites on protein targets, as well as evidence that binding to some proteins is better characterized by an interaction region that can accommodate multiple molecules of ethanol.

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“…These studies at 12 ATA and lower demonstrate that pressure antagonism meets the key criteria for a direct mechanism (Syapin et al , 1988;Bejanian et al , 1993;Davies et al , 1994;Syapin et al , 1996;Davies et al , 1999;Davies and Alkana, 2001;Malcolm and Alkana, 1982;Alkana and Malcolm, 1982b;Alkana and Malcolm, 1982a;Davies et al , 2003) and selectivity (Alkana et al , 1995;Davies and Alkana, 1998;Davies et al , 1996;Davies and Alkana, 1998;Davies et al , 2001;Davies et al , 1999;Davies et al , 2003), necessary for it to be used in a manner analogous to a traditional pharmacological antagonist to help identify initial molecular sites of ethanol action and to test cause-effect relationships (Davies and Alkana, 2001). From this perspective, the sites of pressure antagonism are the same as the sites of ethanol action.…”

Section: Introductionmentioning

confidence: 86%

“…Studies show that exposure to 4–12 times normal atmospheric pressure (ATA) is a direct ethanol antagonist that blocks and reverses a broad spectrum of ethanol’s acute and chronic behavioral effects (Alkana and Malcolm, 1981;Alkana and Malcolm, 1982a;Malcolm and Alkana, 1982;Alkana et al , 1992;Nielsen et al , 1987;Bejanian et al , 1993;Davies et al , 1994;Davies et al , 1999;Davies and Alkana, 2001), as well as its effects at the biochemical (Davies and Alkana, 1998;Davies et al , 1999;Davies and Alkana, 2001) and molecular (Davies et al , 2003;Davies et al , 2004;Perkins et al , 2008) levels.…”

Section: Introductionmentioning

confidence: 99%

Molecular targets and mechanisms for ethanol action in glycine receptors

Perkins¹,

Trudell²,

Crawford³

et al. 2010

Pharmacology & Therapeutics

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Glycine receptors (GlyRs) are recognized as the primary mediators of neuronal inhibition in the spinal cord, brain stem and higher brain regions known to be sensitive to ethanol. Building evidence supports the notion that ethanol acting on GlyRs causes at least a subset of its behavioral effects and may be involved in modulating ethanol intake. For over two decades, GlyRs have been studied at the molecular level as targets for ethanol action. Despite the advances in understanding the effects of ethanol in vivo and in vitro, the precise molecular sites and mechanisms of action for ethanol in ligand-gated ion channels in general, and in GlyRs specifically, are just now starting to become understood. The present review focuses on advances in our knowledge produced by using molecular biology, pressure antagonism, electrophysiology and molecular modeling strategies over the last two decades to probe, identify and model the initial molecular sites and mechanisms of ethanol action in GlyRs. The molecular targets on the GlyR are covered on a global perspective, which includes the intracellular, transmembrane and extracellular domains. The latter has received increasing attention in recent years. Recent molecular models of the sites of ethanol action in GlyRs and their implications to our understanding of possible mechanism of ethanol action and novel targets for drug development in GlyRs are discussed.

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Low‐Level Hyperbaric Antagonism of Ethanol‐Induced Locomotor Depression in C57BL/6J Mice: Dose Response

Cited by 15 publications

References 27 publications

Multiple sites of ethanol action in α1 and α2 glycine receptors suggested by sensitivity to pressure antagonism

Multiple sites of ethanol action in α1 and α2 glycine receptors suggested by sensitivity to pressure antagonism

Alcohol-Binding Sites in Distinct Brain Proteins: The Quest for Atomic Level Resolution

Molecular targets and mechanisms for ethanol action in glycine receptors

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