The Role of Protein Kinase A in Acute Ethanol-Induced Neurobehavioral Actions in Rats

Lai, Chih-Chia; Kuo, Ting-In; Lin, Hsun-Hsun

doi:10.1213/01.ane.0000263030.13249.36

Cited by 29 publications

(29 citation statements)

References 30 publications

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“…Infusion of Sp-cAMP into the lateral ventricles prior to systemic ethanol administration increased the duration of loss of righting reflex (Kumar et al, 2012). Conversely, inhibition of PKA prior to ethanol administration decreased loss of righting reflex duration (Lai et al, 2007) and withdrawal-induced anxiety . Studies utilizing mutant mouse lines with reduced PKA activity mimic results found with pharmacological inhibition of PKA (Thiele et al, 2000;Naassila et al, 2002;Kim et al, 2011).…”

Section: Discussionmentioning

confidence: 92%

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Ethanol Activation of Protein Kinase A Regulates GABA_Aα1 Receptor Function and Trafficking in Cultured Cerebral Cortical Neurons

Carlson

Kumar

Werner

et al. 2013

J Pharmacol Exp Ther

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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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Section: Discussionmentioning

confidence: 92%

“…In vivo studies implicate PKA as playing a role in the behavioral effects of ethanol (Thiele et al, 2000;Pandey et al, 2003;Lai et al, 2007). Additionally, PKA has been shown to directly phosphorylate and modulate GABA A receptor activity (Ives et al, 2002;Brandon et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

Ethanol Activation of Protein Kinase A Regulates GABA_Aα1 Receptor Function and Trafficking in Cultured Cerebral Cortical Neurons

Carlson

Kumar

Werner

et al. 2013

J Pharmacol Exp Ther

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“…Moreover, these signal transduction pathways have been implicated in the actions of ethanol (Moore et al, 1998;Lai et al, 2007). If ethanol exerts its effects on neurotransmitter release through these pathways, we could expect that preactivation of these pathways would occlude the action of ethanol.…”

Section: Resultsmentioning

confidence: 99%

“…Because both cAMP-regulated systems (Moore et al, 1998;Lai et al, 2007) and those systems regulated by phorbol esters (Fehr et al, 2005) have been implicated as potential targets for ethanol, we decided to investigate the potential involvement of ethanol in these pathways. However, we found that neither pretreatment with the adenylate cyclase activator forskolin nor with phorbol dibutryate had any measurable effect on the degree by which neurotransmitter release was potentiated by ethanol, suggesting that neither system is involved in the acute effects of ethanol on neurotransmitter release at the skeletal neuromuscular junction.…”

Section: Discussionmentioning

confidence: 99%

The Mechanism for Prejunctional Enhancement of Neuromuscular Transmission by Ethanol in the Mouse

Searl

Silinsky²

2010

J Pharmacol Exp Ther

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Ethanol has been shown to have both presynaptic and postsynaptic effects on synaptic transmission. However, the mechanisms by which ethanol affects evoked neurotransmitter release have not been studied at the mouse neuromuscular junction, a synapse at which binomial analysis of neurotransmitter release and measurements of prejunctional ionic currents can be made. Ethanol (400 mM) increased neurotransmitter release independently of both the cAMP and phorbol ester/Munc13 signaling pathways. Binomial analysis of neurotransmitter release revealed that ethanol increases the average probability of secretion without an effect on the immediately available store of the neurotransmitter. Application of ethanol also resulted in an inhibition of potassium currents in the motor nerve endings. These results suggest that the potentiating effects of ethanol on neurotransmitter release at the skeletal neuromuscular junction are mediated by an inhibition of the delayed rectifier potassium current, thus increasing both calcium entry into the nerve ending and the probability of neurotransmitter release. Identifying the mechanism through which ethanol enhances neurotransmitter release at the neuromuscular junction may be useful in determining the processes underlying the enhancement of neurotransmitter release at other synapses.

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“…For instance, gene knockout and pharmacological inhibition of the PKA pathway reduces sensitivity to the sedative-hypnotic effects of ethanol (Lai, Kuo, & Lin, 2007; Thiele et al, 2000). Hypnotic sensitivity may be modulated by specific regions, as studies suggest the cerebral cortex is involved, as assessed by using LORR, an assay that also serves as a gauge for overt ethanol sensitivity (Blednov et al, 2011; Blednov & Harris, 2009; Franks & Lieb, 1990).…”

Section: Introductionmentioning

confidence: 99%

Adolescent and adult rat cortical protein kinase A display divergent responses to acute ethanol exposure

Gigante

Santerre

Carter

et al. 2014

Alcohol

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Adolescent rats display reduced sensitivity to many dysphoria-related effects of alcohol (ethanol) including motor ataxia and sedative hypnosis, but the underlying neurobiological factors that contribute to these differences remain unknown. The cyclic adenosine monophosphate (cAMP)-dependent protein kinase A (PKA) pathway, particularly the type II regulatory subunit (RII), has been implicated in ethanol-induced molecular and behavioral responses in adults. Therefore, the current study examined cerebral cortical PKA in adolescent and adult ethanol responses. With the exception of early adolescence, PKA RIIα and RIIβ subunit levels largely did not differ from adult levels in either whole cell lysate or P2 synaptosomal expression. However, following acute ethanol exposure, PKA RIIβ P2 synaptosomal expression and activity were increased in adults, but not in adolescents. Behaviorally, intracerebroventricular administration of the PKA activator Sp-cAMP and inhibitor Rp-cAMP prior to ethanol administration increased adolescent sensitivity to the sedative-hypnotic effects of ethanol compared to controls. Sp-cAMP was ineffective in adults whereas Rp-cAMP suggestively reduced loss of righting reflex (LORR) with paralleled increases in blood ethanol concentrations. Overall, these data suggest that PKA activity modulates the sedative/hypnotic effects of ethanol and may potentially play a wider role in the differential ethanol responses observed between adolescents and adults.

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The Role of Protein Kinase A in Acute Ethanol-Induced Neurobehavioral Actions in Rats

Abstract: Our results suggest that the PKA pathway may participate in ethanol-induced neurobehavioral changes and that NMDA receptors may be involved in the PKA regulation of ethanol's actions.

Cited by 29 publications

References 30 publications

Ethanol Activation of Protein Kinase A Regulates GABA_Aα1 Receptor Function and Trafficking in Cultured Cerebral Cortical Neurons

Ethanol Activation of Protein Kinase A Regulates GABA_Aα1 Receptor Function and Trafficking in Cultured Cerebral Cortical Neurons

The Mechanism for Prejunctional Enhancement of Neuromuscular Transmission by Ethanol in the Mouse

Adolescent and adult rat cortical protein kinase A display divergent responses to acute ethanol exposure

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The Role of Protein Kinase A in Acute Ethanol-Induced Neurobehavioral Actions in Rats

Abstract: Our results suggest that the PKA pathway may participate in ethanol-induced neurobehavioral changes and that NMDA receptors may be involved in the PKA regulation of ethanol's actions.

Cited by 29 publications

References 30 publications

Ethanol Activation of Protein Kinase A Regulates GABAAα1 Receptor Function and Trafficking in Cultured Cerebral Cortical Neurons

Ethanol Activation of Protein Kinase A Regulates GABAAα1 Receptor Function and Trafficking in Cultured Cerebral Cortical Neurons

The Mechanism for Prejunctional Enhancement of Neuromuscular Transmission by Ethanol in the Mouse

Adolescent and adult rat cortical protein kinase A display divergent responses to acute ethanol exposure

Contact Info

Product

Resources

About

Ethanol Activation of Protein Kinase A Regulates GABA_Aα1 Receptor Function and Trafficking in Cultured Cerebral Cortical Neurons

Ethanol Activation of Protein Kinase A Regulates GABA_Aα1 Receptor Function and Trafficking in Cultured Cerebral Cortical Neurons