The effects of acute and chronic ethanol exposure on presynaptic and postsynaptic gamma-aminobutyric acid (GABA) neurotransmission in cultured cortical and hippocampal neurons

Fleming, Rebekah L.; Manis, Paul B.; Morrow, A. Leslie

doi:10.1016/j.alcohol.2009.10.006

Cited by 31 publications

(32 citation statements)

References 64 publications

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“…Alcohol-related behaviors represent an interesting example of preclinical studies. Acute exposure to ethanol potentiates GABA A receptor function by complex effects on pre-and postsynaptic elements of GABAergic synapses (Fleming et al, 2009) and accordingly, induces a CNS depression secondary to enhanced inhibitory transmission. On the other hand, chronic ethanol exposure seems to induce compensatory adaptations to the acute facilitatory effects of ethanol on GABAergic synapses (Steffensen et al, 2009;Diana et al, 2003), such as marked changes in the expression of specific GABA A receptor subunits and alterations in the subunit composition of these receptors, which are primarily responsible for alterations in GABAergic signalling associated with chronic ethanol exposure (Weiner and Valenzuela, 2006).…”

Section: Gaba As a Therapeutic Target For Addictionmentioning

confidence: 99%

Novel Therapeutic Strategies for Alcohol and Drug Addiction: Focus on GABA, Ion Channels and Transcranial Magnetic Stimulation

Addolorato

Leggio

Hopf

et al. 2011

Neuropsychopharmacol

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Drug addiction represents a major social problem where addicts and alcoholics continue to seek and take drugs despite adverse social, personal, emotional, and legal consequences. A number of pharmacological compounds have been tested in human addicts with the goal of reducing the level or frequency of intake, but these pharmacotherapies have often been of only moderate efficacy or act in a sub-population of humans. Thus, there is a tremendous need for new therapeutic interventions to treat addiction. Here, we review recent interesting studies focusing on gamma-aminobutyric acid receptors, voltage-gated ion channels, and transcranial magnetic stimulation. Some of these treatments show considerable promise to reduce addictive behaviors, or the early clinical studies or pre-clinical rationale suggest that a promising avenue could be developed. Thus, it is likely that within a decade or so, we could have important new and effective treatments to achieve the goal of reducing the burden of human addiction and alcoholism.

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Section: Gaba As a Therapeutic Target For Addictionmentioning

confidence: 99%

Novel Therapeutic Strategies for Alcohol and Drug Addiction: Focus on GABA, Ion Channels and Transcranial Magnetic Stimulation

Addolorato

Leggio

Hopf

et al. 2011

Neuropsychopharmacol

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“…As ethanol exposure has been shown to alter mIPSC decay kinetics, which is related to changes in GABA A receptor subunit expression (Liang et al, 2006;Fleming et al, 2009;Werner et al, 2011), recordings of mIPSCs were made to further investigate the functional consequences of ethanol activation of PKA on synaptic GABA A receptor signaling. Although there appeared to be a slight shift in the mIPSC decay kinetics suggestive of an altered synaptic GABA A receptor expression profile, there was not a significant direct effect of 1 hour ethanol and/or PKA modulation on GABA mIPSC kinetics ( Fig.…”

Section: Pka Activation By Ethanol Regulates Zolpidemmentioning

confidence: 99%

Ethanol Activation of Protein Kinase A Regulates GABAA α1 Receptor Function and Trafficking in Cultured Cerebral Cortical Neurons

Carlson

Kumar

Werner

et al. 2013

The Journal of Pharmacology and Experimental Therapeutics

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Ethanol exposure produces alterations in GABAergic signaling that are associated with dependence and withdrawal. Previously, we demonstrated that ethanol-induced protein kinase C (PKC) g signaling selectively contributes to changes in GABA A a1 synaptic receptor activity and surface expression. Here, we demonstrate that protein kinase A (PKA) exerts opposing effects on GABA A receptor adaptations during brief ethanol exposure. Cerebral cortical neurons from day 0-1 rat pups were tested after 18 days in culture. Receptor trafficking was assessed by Western blot analysis, and functional changes were measured using whole-cell patch-clamp recordings of evoked and miniature inhibitory postsynaptic current (mIPSC) responses. Onehour ethanol exposure increased membrane-associated PKC and PKA, but steady-state GABA A a1 subunit levels were maintained.Activation of PKA by Sp-adenosine 39,59-cyclic monophosphothioate triethylamine alone increased GABA A a1 subunit surface expression and zolpidem potentiation of GABA responses, whereas coexposure of ethanol with the PKA inhibitor Rp-adenosine 39,59-cyclic monophosphothioate triethylamine decreased a1 subunit expression and zolpidem responses. Exposure to the PKC inhibitor calphostin-C with ethanol mimicked the effect of direct PKA activation. The effects of PKA modulation on mIPSC decay t were consistent with its effects on GABA currents evoked in the presence of zolpidem. Overall, the results suggest that PKA acts in opposition to PKC on a1-containing GABA A receptors, mediating the GABAergic effects of ethanol exposure, and may provide an important target for the treatment of alcohol dependence/withdrawal.

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“…The results suggest that EtOH exposure in vitro has limited effects on synaptic GABA A R function and action potentialindependent GABA release in cultured neurons. This group also investigated the effect of chronic EtOH exposure on GABA release in cultured hippocampal neurons (Fleming et al 2009). These investigators found that chronic EtOH exposure did not alter mIPSC kinetics and frequencies in hippocampal neurons (Fleming et al 2009).…”

Section: Chronic Ethanol and Gabaergic Transmission: Presynaptic Effectsmentioning

confidence: 99%

“…This group also investigated the effect of chronic EtOH exposure on GABA release in cultured hippocampal neurons (Fleming et al 2009). These investigators found that chronic EtOH exposure did not alter mIPSC kinetics and frequencies in hippocampal neurons (Fleming et al 2009). These results suggest that EtOH exposure in cultured cortical and hippocampal neurons may not reproduce all the effects that occur in vivo and in acute brain slices.…”

Section: Chronic Ethanol and Gabaergic Transmission: Presynaptic Effectsmentioning

confidence: 99%

“…Short in vitro chronic EtOH exposure (one day) induced a transient decrease in mIPSC duration in cultured cortical neurons. Chronic EtOH exposure did not change mIPSC frequency nor did it produce a substantial cross-tolerance to a benzodiazepine in cortical neurons (Fleming et al 2009). The results suggest that EtOH exposure in vitro has limited effects on synaptic GABA A R function and action potentialindependent GABA release in cultured neurons.…”

Section: Chronic Ethanol and Gabaergic Transmission: Presynaptic Effectsmentioning

confidence: 99%

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Synaptic Effects Induced by Alcohol

Lovinger

Roberto

2010

Current Topics in Behavioral Neurosciences

117

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Ethanol (EtOH) has effects on numerous cellular molecular targets, and alterations in synaptic function are prominent among these effects. Acute exposure to EtOH activates or inhibits the function of proteins involved in synaptic transmission, while chronic exposure often produces opposing and/or compensatory/homeostatic effects on the expression, localization, and function of these proteins. Interactions between different neurotransmitters (e.g., neuropeptide effects on release of small molecule transmitters) can also influence both acute and chronic EtOH actions. Studies in intact animals indicate that the proteins affected by EtOH also play roles in the neural actions of the drug, including acute intoxication, tolerance, dependence, and the seeking and drinking of EtOH. This chapter reviews the literature describing these acute and chronic synaptic effects of EtOH and their relevance for synaptic transmission, plasticity, and behavior. KeywordsGABA; Glutamate; Monoamine; Neuropeptide; Neurotransmitter receptor; Presynaptic; Postsynaptic; Protein phosphorylation; Synaptic plasticity; Intoxication; Tolerance; Dependence Acute Ethanol ActionsEthanol (EtOH) produces intoxication through actions on the central nervous system (CNS) at concentrations ranging from low to ~100 mM (at least in non-tolerant humans and experimental animals). A number of proteins involved in synaptic transmission are altered by EtOH effects within this concentration range. The target proteins include, but are not limited to, ion channels, neurotransmitter receptors, and intracellular signaling proteins. The first section of this article will review the literature describing the most prominent acute EtOH effects on synaptic transmission in the CNS. This review is not meant to be comprehensive, but rather to cover those effects that have been observed most consistently and are thought to contribute to intoxication.

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The effects of acute and chronic ethanol exposure on presynaptic and postsynaptic gamma-aminobutyric acid (GABA) neurotransmission in cultured cortical and hippocampal neurons

Cited by 31 publications

References 64 publications

Novel Therapeutic Strategies for Alcohol and Drug Addiction: Focus on GABA, Ion Channels and Transcranial Magnetic Stimulation

Novel Therapeutic Strategies for Alcohol and Drug Addiction: Focus on GABA, Ion Channels and Transcranial Magnetic Stimulation

Ethanol Activation of Protein Kinase A Regulates GABAA α1 Receptor Function and Trafficking in Cultured Cerebral Cortical Neurons

Synaptic Effects Induced by Alcohol

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