Genetically Determined Differences in the Antagonistic Effect of Pressure on Ethanol‐Induced Loss of Righting Reflex in Mice

Alkana, Ronald L.; Finn, Deborah A.; Jones, Brenda L.; Kobayashi, Leigh S.; Babbini, M.; Bejanian, Marina; Syapin, Peter J.

doi:10.1111/j.1530-0277.1992.tb00629.x

Cited by 12 publications

(15 citation statements)

References 38 publications

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“…Subsequent experiments determined that the non‐specific excitatory effects attributed to pressures above 50 ATA could be eliminated by using lower levels of hyperbaric exposure. 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 .…”

Section: Discussionmentioning

confidence: 99%

“…Prior studies have shown that exposure to 12 times normal atmospheric pressure (ATA) of helium‐oxygen gas (heliox) directly antagonizes the behavioral and biochemical actions of ethanol (Alkana and Malcolm 1981; Alkana et al . 1992; Bejanian et al .…”

mentioning

confidence: 99%

“…Prior studies have shown that exposure to 12 times normal atmospheric pressure (ATA) of helium-oxygen gas (heliox) directly antagonizes the behavioral and biochemical actions of ethanol (Alkana and Malcolm 1981;Alkana et al 1992;Bejanian et al 1993;Alkana 1998, 2001). More recent two-electrode voltage clamp studies demonstrated that pressure antagonized ethanol potentiation (50-200 mM) of a1 GlyR function in a direct, reversible, concentration and pressure dependent manner (Davies et al 2003).…”

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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%

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confidence: 99%

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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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“…DHβE doses (1.0 – 3.0 mg/kg) were based on published and unpublished studies from our lab that were within an effective range of doses for blocking the behavioral effects of nicotine (Damaj et al 1995, 2003). Ethanol doses (2.0 – 3.5 g/kg) were chosen based on active doses in previous studies (Alanka et al 1992, Browman et al 2000). …”

Section: Methodsmentioning

confidence: 99%

The β2 nicotinic acetylcholine receptor subunit differentially influences ethanol behavioral effects in the mouse

Dawson

Miles

Damaj

2013

Alcohol

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The high co-morbidity between alcohol (ethanol) and nicotine abuse suggests that nicotinic acetylcholine receptors (nAChRs), thought to underlie nicotine dependence, may also be involved in alcohol dependence. The β2* nAChR subtype serves as a potential interface for these interactions since they are the principle mediators of nicotine dependence and have recently been shown to modul6ate some acute responses to ethanol. Therefore, the aim of this study was to more fully characterize the role of β2* nAChRs in ethanol-responsive behaviors in mice after acute exposure to the drug. We conducted a battery of tests in mice lacking the β2 coding gene (Chrnb2) or pretreated with a selective β2* nAChR antagonist for a range of ethanol-induced behaviors including locomotor depression, hypothermia, hypnosis, and anxiolysis. We also tested the effect of deletion on voluntary escalated ethanol consumption in an intermittent access two-bottle choice paradigm to determine the extent of these effects on drinking behavior. Our results showed that antagonism of β2* nAChRs modulated some acute behaviors, namely by reducing recovery time from hypnosis and enhancing the anxiolytic-like response produced by acute ethanol in mice. Chrnb2 deletion had no effect on ethanol drinking behavior, however. We provide further evidence that β2* nAChRs have a measurable role in mediating specific behavioral effects induced by acute ethanol exposure without affecting drinking behavior directly. We conclude that these receptors, along with being key components in nicotine dependence, may also present viable candidates in the discovery of the molecular underpinnings of alcohol dependence.

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“…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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Genetically Determined Differences in the Antagonistic Effect of Pressure on Ethanol‐Induced Loss of Righting Reflex in Mice

Cited by 12 publications

References 38 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

The β2 nicotinic acetylcholine receptor subunit differentially influences ethanol behavioral effects in the mouse

Molecular targets and mechanisms for ethanol action in glycine receptors

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