Alcohol-sensitive GABA receptors and alcohol antagonists

Paul, Steven M.

doi:10.1073/pnas.0602862103

Cited by 35 publications

(35 citation statements)

References 22 publications

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“…While there may still be some concerns whether or not inverse agonist activity of Ro15-4513 might contribute to its alcohol antagonist effect, our data combined with previous work on behavioral alcohol reversal effect of Ro15-4513 very strongly implicate unique types of GABA A Rs as mediating important low dose alcohol actions (Paul, 2006). In fact the pharmacological resemblance of ethanol actions on recombinant receptors with behavioral actions -all ligands that have been previously shown to inhibit Ro15-4513's alcohol antagonism (flumazenil, β-CCE, FG7142) also have < 10 nM affinity for this binding siteprovides unique evidence that EtOH/Ro15-4513-ensitive GABA A Rs are important mediators of low to moderate dose alcohol actions (Paul, 2006).…”

Section: Interactions Of Alcohol and The Benzodiazepine Behavioral Alsupporting

confidence: 52%

“…In fact the pharmacological resemblance of ethanol actions on recombinant receptors with behavioral actions -all ligands that have been previously shown to inhibit Ro15-4513's alcohol antagonism (flumazenil, β-CCE, FG7142) also have < 10 nM affinity for this binding siteprovides unique evidence that EtOH/Ro15-4513-ensitive GABA A Rs are important mediators of low to moderate dose alcohol actions (Paul, 2006).…”

Section: Interactions Of Alcohol and The Benzodiazepine Behavioral Almentioning

confidence: 99%

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GABAA receptor subtypes: the “one glass of wine” receptors

Olsen

Hanchar

Meera

et al. 2007

Alcohol

128

121

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This review discusses evidence for and apparent controversy about, GABA A receptor subtypes that mediate alcohol effects experienced during social drinking. GABA A receptors that contain the β3 and δ subunits were shown to be enhanced by alcohol concentrations that mirror the concentrationdependence of alcohol responses in humans. A mutation (α6R100Q) previously found in alcohol non-tolerant (ANT) rats in the cerebellar GABA A receptor α6 subunit is sufficient for increased alcohol-induced ataxia in rats homozygous for this mutation (α6-100QQ) and further increases alcohol-sensitivity of tonic GABA currents (mediated by α6βδ receptors) in cerebellar granule cells of α6-100QQ rats and in recombinant α6R100Qβ3δ receptors. This provided the first direct evidence that these types of receptors mediate behavioral effects of ethanol. Furthermore the behavioral alcohol antagonist Ro15-4513 specifically reverses ethanol enhancement on α4/6β3δ receptors. Unexpectedly, native and recombinant α4/6β3δ receptors bind the behavioral alcohol antagonist Ro15-4513 with high affinity and this binding is competitive with EtOH, suggesting a specific and mutually exclusive (competitive) ethanol/Ro15-4513 site which explains the puzzling activity of Ro15-4513 as a behavioral alcohol antagonist.Our conclusion from these findings is that alcohol/Ro15-4513-sensitive GABA A receptor subtypes are important alcohol targets and that alcohol at relevant concentrations is more specific than previously thought. In this review we discuss technical difficulties in expressing recombinant δ subunit-containing receptors in oocytes and mammalian cells, that may have contributed to negative results and confusion. Not only because we have reproduced detailed positive results numerous times, and we and many others have built extensively on basic findings, but also because we explain and combine many previously puzzling results into a coherent and highly plausible paradigm on how alcohol exerts an important part of its action in the brain, we are confident about our findings and conclusions. However, many important open questions remain to be answered.

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Section: Interactions Of Alcohol and The Benzodiazepine Behavioral Alsupporting

confidence: 52%

Section: Interactions Of Alcohol and The Benzodiazepine Behavioral Almentioning

confidence: 99%

GABAA receptor subtypes: the “one glass of wine” receptors

Olsen

Hanchar

Meera

et al. 2007

Alcohol

128

121

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“…This is consistent with the previous observations that on its own, DHM is not anxiolytic, or sedative, or proconvulsant at the dose (1 mg/kg) that blocks EtOH effects on GABA A Rs in adult male rats [26]. This contrasts DHM with Ro15-4513, which was shown to block EtOH's enhancement of GABA A Rs in vitro and in vivo [131,132] and shown to also possess both pro-convulsant and anxiogenic effects due to its ability to block most GABA A R subtypes [133]. DHM was also shown to greatly reduce EtOH consumption when high voluntary EtOH consumption is already established in adult male rats [26], suggesting that similar reductions in voluntary EtOH consumption could be achieved in females.…”

mentioning

confidence: 99%

Dihydromyricetin Prevents Fetal Alcohol Exposure-Induced Behavioral and Physiological Deficits: The Roles of GABAA Receptors in Adolescence

et al. 2014

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Fetal alcohol exposure (FAE) can lead to a variety of behavioral and physiological disturbances later in life. Understanding how alcohol (ethanol, EtOH) affects fetal brain development is essential to guide the development of better therapeutics for FAE. One of EtOH's many pharmacological targets is the c-aminobutyric acid type A receptor (GABA A R), which plays a prominent role in early brain development. Acute EtOH potentiates inhibitory currents carried by certain GABA A R subtypes, whereas chronic EtOH leads to persistent alterations in GABA A R subunit composition, localization and function. We recently introduced a flavonoid compound, dihydromyricetin (DHM), which selectively antagonizes EtOH's intoxicating effects in vivo and in vitro at enhancing GABA A R function as a candidate for alcohol abuse pharmacotherapy. Here, we studied the effect of FAE on physiology, behavior and GABA A R function of early adolescent rats and tested the utility of DHM as a preventative treatment for FAE-induced disturbances. Gavage administration of EtOH (1.5, 2.5, or 5.0 g/kg) to rat dams on day 5, 8, 10, 12, and 15 of pregnancy dose-dependently reduced female/male offspring ratios (largely through decreased numbers of female offspring) and offspring body weights. FAE (2.5 g/kg) rats tested on postnatal days (P) 25-32 also exhibited increased anxiety and reduced pentylenetetrazol (PTZ)-induced seizure threshold. Patchclamp recordings from dentate gyrus granule cells (DGCs) in hippocampal slices from FAE (2.5 g/kg) rats at P25-35 revealed reduced sensitivity of GABAergic miniature inhibitory postsynaptic currents (mIPSCs) and tonic current (I tonic ) to potentiation by zolpidem (0.3 lM). Interestingly, potentiation of mIPSCs by gaboxadol increased, while potentiation of I tonic decreased in DGCs from FAE rats. Coadministration of EtOH (1.5 or 2.5 g/kg) with DHM (1.0 mg/kg) in pregnant dams prevented all of the behavioral, physiological, and pharmacological alterations observed in FAE offspring. DHM administration alone in pregnant rats had no adverse effect on litter size, progeny weight, anxiety level, PTZ seizure threshold, or DGC GABA A R function. Our results indicate that FAE induces long-lasting alterations in physiology, behavior, and hippocampal GABA A R function and that these deficits are prevented by DHM co-treatment of EtOH-exposed dams. The absence of adverse side effects and the ability of DHM to prevent FAE consequences suggest that DHM is an attractive candidate for development as a treatment for prevention of fetal alcohol spectrum disorders.

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“…Recombinant GABA A Rs expressing the α6R100Qβ3δ in oocytes also showed higher sensitivity to EtOH modulation (1-10 mM) than the already sensitive WT α6R100β3δ (10-30 mM) (7). Second, the residue R100 in the GABA A R α-subunit that affects EtOH sensitivity is part of the benzodiazepine ligand-binding pocket on the α6-subunit, consistent not only with the discovery of a previously unappreciated benzodiazepine (BZ) site on the δ-subunit-containing GABA A Rs but with the demonstration that these unique BZ sites mediate antagonism by the BZ ligand Ro15-4513 of in vivo EtOH behaviors (10) and in vitro antagonism of low-to moderate-dose EtOH enhancement of δ-subunit-containing GABA A Rs (7). Third, the observation that the α4βδ GABA A R subtypes are the most rapidly regulated in plastic mechanisms triggered by high-dose EtOH or chronic exposure to EtOH in rats (8) is consistent with these extrasynaptic GABA A Rs being among the first responders to EtOH in the brain.…”

mentioning

confidence: 62%

Extrasynaptic GABA _A receptors in the nucleus accumbens are necessary for alcohol drinking

Olsen

2011

Proc. Natl. Acad. Sci. U.S.A.

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Alcohol-sensitive GABA receptors and alcohol antagonists

Cited by 35 publications

References 22 publications

GABAA receptor subtypes: the “one glass of wine” receptors

GABAA receptor subtypes: the “one glass of wine” receptors

Dihydromyricetin Prevents Fetal Alcohol Exposure-Induced Behavioral and Physiological Deficits: The Roles of GABAA Receptors in Adolescence

Extrasynaptic GABA _A receptors in the nucleus accumbens are necessary for alcohol drinking

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Alcohol-sensitive GABA receptors and alcohol antagonists

Cited by 35 publications

References 22 publications

GABAA receptor subtypes: the “one glass of wine” receptors

GABAA receptor subtypes: the “one glass of wine” receptors

Dihydromyricetin Prevents Fetal Alcohol Exposure-Induced Behavioral and Physiological Deficits: The Roles of GABAA Receptors in Adolescence

Extrasynaptic GABA A receptors in the nucleus accumbens are necessary for alcohol drinking

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Extrasynaptic GABA _A receptors in the nucleus accumbens are necessary for alcohol drinking