Genotype-dependent effects of GABAergic agents on sedative properties of ethanol

Dudek, Bruce C.; Phillips, Tamara J.

doi:10.1007/bf00441952

Cited by 13 publications

(6 citation statements)

References 25 publications

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“…l) replicated the findings of our earlier studies (experiment 1 and Dudek and Phillips, 1989) and were remarkably similar to comparisons of SK and LS mice (Fig. 3).…”

Section: Ss and Ls Micesupporting

confidence: 91%

Modification of ethanol effects by bicuculline: genotype-dependent responses and inheritance

Phillips

Dudck

1989

Psychopharmacology

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Genetic influences on the interaction between ethanol (ETOH) and gamma-aminobutyric acid (GABA) neurotransmitter systems were evaluated with a survey of responses to coadministration of ETOH and a GABA antagonist, bicuculline, in a battery of inbred mouse strains. The selectively bred ETOH-sensitive Long-Sleep (LS) mice, the relatively ETOH-resistant Short-Sleep (SS) mice, and a genetically heterogeneous stock (GHS) were also evaluated. The effect of bicuculline on ETOH-induced sedation, hypothermia, and blood ethanol content upon recovery from sedation was assessed. Inheritance of these responses was also examined using F1 hybrids. The effect of bicuculline on ETOH-produced narcosis varied widely among stocks and included antagonism, potentiation, and no effect. Changes in ETOH-induced narcosis produced by bicuculline were accompanied by changes in blood ethanol concentrations consistent with an hypothesis of altered central nervous system sensitivity to ETOH. Knowledge of a strain's seizure susceptibility to the GABA antagonist or of its sensitivity to the hypnotic effects of ETOH were of no predictive value in estimating the outcome of coadministration studies, suggesting at least partially separate genetic influences on each phenotype. In cross-breeding studies there was commonly dominance toward a profile of bicuculline antagonism of ETOH narcosis but different patterns of dominance were observed for seizure susceptibility, again indicating separate genetic control. The results suggest considerable complexity of GABAergic involvement in genotype-dependent ETOH sensitivity.

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“…l) replicated the findings of our earlier studies (experiment 1 and Dudek and Phillips, 1989) and were remarkably similar to comparisons of SK and LS mice (Fig. 3).…”

Section: Ss and Ls Micesupporting

confidence: 91%

Modification of ethanol effects by bicuculline: genotype-dependent responses and inheritance

Phillips

Dudck

1989

Psychopharmacology

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“…This absence of an effect on of Glo1 manipulations on ethanol locomotor response, especially ethanol locomotor sedation, is surprising given the considerable literature showing that other GABAergic drugs act synergistically with ethanol to potentiate sedative effects (e.g. Tran et al, 2017;Vanover et al, 1999;Saeed Dar, 2006;Holstein et al, 2009;Dudek & Phillips, 1989).…”

Section: Discussionmentioning

confidence: 97%

“…Specifically, it has been well-established that enhanced locomotor sedation and ataxia is observed when ethanol and GABAergic agonists or positive modulators are co-administered (e.g. Tran et al, 2017;Vanover et al, 1999;Saeed Dar, 2006;Holstein et al, 2009;Dudek & Phillips, 1989). Additive locomotor effects with ethanol could potentially explain a compound's ability to reduce ethanol consumption due to an increase in competing behaviors (e.g.…”

Section: Introductionmentioning

confidence: 99%

Glyoxalase (GLO1) inhibition or genetic overexpression does not alter ethanol’s locomotor effects: implications for GLO1 as a therapeutic target in alcohol use disorders

Barkley-Levenson

Lagarda

Palmer

2017

Preprint

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Background: Glyoxalase 1 (GLO1) is an enzyme that metabolizes the glycolytic byproduct methylglyoxal (MG), which is a competitive partial agonist at GABAA receptors.Pharmacological inhibition of GLO1 increases concentrations of MG in the brain and decreases binge-like ethanol drinking. The present study assessed whether pharmacological inhibition of GLO1, or genetic over expression of Glo1, would also alter the locomotor effects of ethanol, which might explain reduced ethanol consumption following GLO1 inhibition. We used the prototypical GABAA receptor agonist muscimol as a positive control.Methods: Male C57BL/6J mice were pretreated with a single dose of either the GLO1 inhibitor S-bromobenzylglutathione cyclopentyl diester (pBBG; 7.5 mg/kg; Experiment 1) or muscimol (0.75 mg/kg; Experiment 2), or their corresponding vehicle. We then determined whether the locomotor response to a range of ethanol doses (0, 0.5, 1.0, 1.5, 2.0, and 2.5) was altered by either pBBG or muscimol pretreatment. We also examined the locomotor response to a range of ethanol doses in FVB/NJ wild type and transgenic Glo1 over expressing mice (Experiment 3).We also assessed anxiety-like behavior as measured by time spent in the center of an open field in all three experiments. Results:The ethanol dose-response curve was not altered by pretreatment with pBBG or by transgenic overexpression of Glo1. In contrast, muscimol blunted locomotor stimulation at low ethanol doses, and potentiated locomotor sedation at higher ethanol doses. Conclusions:The dose of pBBG used in this study has been previously shown to reduce ethanol drinking. Glo1 overexpression has been previously shown to increase ethanol drinking.However, neither manipulation altered the dose response curve for ethanol's locomotor effects, whereas muscimol appeared to enhance the locomotor sedative effects of ethanol. The present ! 2 data demonstrate that reduced ethanol drinking caused by GLO1 inhibition is not due to potentiation of ethanol's stimulant or depressant effects.

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“…Substantial previous work with various GABAergic agonists and positive allosteric modulators indicates that compounds that increase GABAergic activity can produce additive effects when administered with EtOH. Specifically, it has been well‐established that enhanced locomotor sedation and ataxia are observed when EtOH and GABAergic agonists or positive modulators are co‐administered (e.g., Dudek and Phillips, ; Holstein et al., ; Saeed Dar, ; Tran et al., ; Vanover et al., ). Additive locomotor effects with EtOH could potentially explain a compound's ability to reduce EtOH consumption due to an increase in competing behaviors (e.g., locomotor activation) or through increased sedative effects that limit consumption.…”

mentioning

confidence: 99%

Glyoxalase 1 (GLO1) Inhibition or Genetic Overexpression Does Not Alter Ethanol's Locomotor Effects: Implications for GLO1 as a Therapeutic Target in Alcohol Use Disorders

Barkley-Levenson

Lagarda

Palmer

2018

Alcoholism Clin & Exp Res

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The dose of pBBG used in this study is within the effective range shown previously to reduce EtOH drinking. Glo1 overexpression has been previously shown to increase EtOH drinking. However, neither manipulation altered the dose-response curve for EtOH's locomotor effects, whereas muscimol appeared to enhance the locomotor sedative effects of EtOH. The present data demonstrate that reduced EtOH drinking caused by GLO1 inhibition is not due to potentiation of EtOH's stimulant or depressant effects.

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Genotype-dependent effects of GABAergic agents on sedative properties of ethanol

Cited by 13 publications

References 25 publications

Modification of ethanol effects by bicuculline: genotype-dependent responses and inheritance

Modification of ethanol effects by bicuculline: genotype-dependent responses and inheritance

Glyoxalase (GLO1) inhibition or genetic overexpression does not alter ethanol’s locomotor effects: implications for GLO1 as a therapeutic target in alcohol use disorders

Glyoxalase 1 (GLO1) Inhibition or Genetic Overexpression Does Not Alter Ethanol's Locomotor Effects: Implications for GLO1 as a Therapeutic Target in Alcohol Use Disorders

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