Behavioral evidence for the involvement of γ-aminobutyric acid in the actions of ethanol

Martz, A; Dietrich, Richard; Harris, R. Adron

doi:10.1016/0014-2999(83)90607-6

Cited by 208 publications

(72 citation statements)

References 30 publications

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“…In addition, it was demonstrated that the GABA A R agonists (e.g., muscimol) potentiated the sedative properties of EtOH, while the opposite effect, a reduction of EtOH-produced sedation or motor-incoordinating effects, was seen upon administration of the GABA A R blocking agents picrotoxin and bicuculline (Hakkinen & Kulonen, 1976;Frye & Breese, 1982;Liljequist & Engel, 1982;Martz et al, 1983). Picrotoxin and bicuculline are not practical clinically as alcohol antagonists, because they lead to life-threatening convulsions.…”

Section: Early Pharmacological Evidence For the Involvement 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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Section: Early Pharmacological Evidence For the Involvement Of Gaba Amentioning

confidence: 99%

Low dose acute alcohol effects on GABAA receptor subtypes

Wallner

Hanchar

Olsen

2006

Pharmacology & Therapeutics

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“…Evidence accumulated over several decades suggested that ethanol influences GABA function (Allan and Harris, 1987;Frye and Breese, 1982;Liljequist and Engel, 1982;Martz et al, 1983;Mereu and Gessa, 1985;Nestoros, 1980;Simson et al, 1991;see Crews et al, 1996). Most convincing was the early recognition that behavioral consequences of moderate doses of ethanol had similarities to those of BZDs and barbiturates (Breese et al, 1983;Frye et al, 1979, White et al, 1997, drugs known to rely on GABA A receptor function (see Harris, 1990;Ticku, 1989).…”

Section: Interaction Of Ethanol With the Gaba System In Vivomentioning

confidence: 99%

“…Most convincing was the early recognition that behavioral consequences of moderate doses of ethanol had similarities to those of BZDs and barbiturates (Breese et al, 1983;Frye et al, 1979, White et al, 1997, drugs known to rely on GABA A receptor function (see Harris, 1990;Ticku, 1989). Further, BZDs and barbiturates enhanced ethanol-induced motor impairment (Martz et al, 1983) and substituted for ethanol in drug discrimination studies (Grant et al, 2000;Shannon et al, 2004). On the other hand, a BZD-inverse agonist minimized ethanol-induced sedation (McCown and Breese, 1989;Suzdak et al, 1986a;Ticku and Kulkarni, 1988) and GABA A receptor antagonists decreased the antipunishment action of ethanol (Koob et al, 1986(Koob et al, , 1988Liljequist and Engel, 1984).…”

Section: Interaction Of Ethanol With the Gaba System In Vivomentioning

confidence: 99%

A Conceptualization of Integrated Actions of Ethanol Contributing to its GABAmimetic Profile: A Commentary

Criswell

Breese

2005

Neuropsychopharmacol

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Early behavioral investigations supported the contention that systemic ethanol displays a GABAmimetic profile. Microinjection of GABA agonists into brain and in vivo electrophysiological studies implicated a regionally specific action of ethanol on GABA function. While selectivity of ethanol to enhance the effect of GABA was initially attributed an effect on type-1-benzodiazepine (BZD)-GABA A receptors, a lack of ethanol's effect on GABA responsiveness from isolated neurons with this receptor subtype discounted this contention. Nonetheless, subsequent work identified GABA A receptor subtypes, with limited distribution in brain, sensitive to enhancement of GABA at relevant ethanol concentrations. In view of these data, it is hypothesized that the GABAmimetic profile for ethanol is due to activation of mechanisms associated with GABA function, distinct from a direct action on the majority of postsynaptic GABA A receptors. The primary action proposed to account for ethanol's regional specificity on GABA transmission is its ability to release GABA from some, but not all, presynaptic GABAergic terminals. As systemic administration of ethanol increases neuroactive steroids, which can enhance GABA responsiveness, this elevated level of neurosteroids is proposed to magnify the effect of GABA released by ethanol. Additional factors contributing to the degree to which ethanol interacts with GABA function include an involvement of GABA B and other receptors that influence ethanol-induced GABA release, an effect of phosphorylation on GABA responsiveness, and a regional reduction of glutamatergic tone. Thus, an integration of these consequences induced by ethanol is proposed to provide a logical basis for its in vivo GABAmimetic profile.

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“…Several ethanol effects are enhanced by the positive GABA A receptor modulators benzodiazepines and barbiturates, but are blocked by GABA A receptor antagonists and inverse agonists (Suzdak et al, 1986a;Nutt and Lister, 1989;Givens and Breese, 1990;Liu and Deitrich, 1998). For example, sedative/hypnotic effects produced by high doses of ethanol are mediated by GABA A receptors and can be enhanced by GABA agonists and blocked by GABA receptor antagonists (Martz et al, 1983). However, the conclusion that ethanol has direct effects on GABA A receptors is controversial.…”

Section: Abstract: Neuroactive Steroids; Ethanol; Allopregnanolone; mentioning

confidence: 99%

Neuroactive Steroid 3α-Hydroxy-5α-Pregnan-20-One Modulates Electrophysiological and Behavioral Actions of Ethanol

VanDoren

Matthews²,

Janis³

et al. 2000

J. Neurosci.

301

293

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Neuroactive steroids are synthesized de novo in brain, yet their physiological significance remains elusive. We provide biochemical, electrophysiological, and behavioral evidence that several specific actions of alcohol (ethanol) are mediated by the neurosteroid 3␣-hydroxy-5␣-pregnan-20-one (3␣,5␣-THP; allopregnanolone). Systemic alcohol administration elevates 3␣,5␣-THP levels in the cerebral cortex to pharmacologically relevant concentrations. The elevation of 3␣,5␣-THP is doseand time-dependent. Furthermore, there is a significant correlation between 3␣,5␣-THP levels in cerebral cortex and the hypnotic effect of ethanol. Blockade of de novo biosynthesis of 5␣-reduced steroids using the 5␣-reductase inhibitor finasteride prevents several effects of ethanol. Pretreatment with finasteride causes no changes in baseline bicuculline-induced seizure threshold but reverses the anticonvulsant effect of ethanol. Finasteride pretreatment also reverses ethanol inhibition of spontaneous neural activity in medial septal/diagonal band of Broca neurons while having no direct effect on spontaneous firing rates. Thus, elevation of 3␣,5␣-THP levels by acute ethanol administration represents a novel mechanism of ethanol action as well as an important modulatory role for neurosteroids in the CNS.

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Behavioral evidence for the involvement of γ-aminobutyric acid in the actions of ethanol

Cited by 208 publications

References 30 publications

Low dose acute alcohol effects on GABAA receptor subtypes

Low dose acute alcohol effects on GABAA receptor subtypes

A Conceptualization of Integrated Actions of Ethanol Contributing to its GABAmimetic Profile: A Commentary

Neuroactive Steroid 3α-Hydroxy-5α-Pregnan-20-One Modulates Electrophysiological and Behavioral Actions of Ethanol

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