Protein kinase C epsilon mediation of CRF- and ethanol-induced GABA release in central amygdala

Bajo, Michal; Cruz, Maureen T.; Siggins, George R.; Messing, Robert O.; Roberto, Marisa

doi:10.1073/pnas.0802302105

Cited by 112 publications

(148 citation statements)

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“…Given the recent evidence that central ghrelin signaling influences alcohol intake (Jerlhag et al, 2009;Kaur and Ryabinin, 2010), we sought to determine whether activation of CeA GHS-R1As by ghrelin would alter the effects of ethanol on GABAergic transmission. To test the influence of GHS-R1A activation on ethanol-induced augmentation of IPSPs, we first superfused a maximal concentration of ghrelin (100-200 nM) onto CeA slices and then added 44 mM ethanol (a dose producing maximal effects; Roberto et al, 2003;Bajo et al, 2008) in the continued presence of ghrelin. We pooled the data from different doses of ghrelin because our dose-response experiments demonstrated that there was no change in the magnitude of effect at these different concentrations (Figure 1c).…”

Section: Acute Ethanol Interacts With Ghrelin Effectsmentioning

confidence: 99%

“…Microinjection of GABA A receptor antagonists into the CeA blocks the reinforcing effect of alcohol (Hyytia and Koob, 1995), and injection of GABA A receptor agonists and benzodiazepines into the CeA decreases anxiety (Roberts et al, 1996), supporting the involvement of the CeA GABAergic system in ethanol reinforcement. We have previously reported that ethanol augments GABAergic transmission in CeA neurons via a presynaptic mechanism that enhances GABA release (Roberto et al, 2003(Roberto et al, , 2010Nie et al, 2004;Bajo et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

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Ghrelin Increases GABAergic Transmission and Interacts with Ethanol Actions in the Rat Central Nucleus of the Amygdala

Cruz

Herman

Cote

et al. 2012

Neuropsychopharmacol

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The neural circuitry that processes natural rewards converges with that engaged by addictive drugs. Because of this common neurocircuitry, drugs of abuse have been able to engage the hedonic mechanisms normally associated with the processing of natural rewards. Ghrelin is an orexigenic peptide that stimulates food intake by activating GHS-R1A receptors in the hypothalamus. However, ghrelin also activates GHS-R1A receptors on extrahypothalamic targets that mediate alcohol reward. The central nucleus of the amygdala (CeA) has a critical role in regulating ethanol consumption and the response to ethanol withdrawal. We previously demonstrated that rat CeA GABAergic transmission is enhanced by acute and chronic ethanol treatment. Here, we used quantitative RT-PCR (qRT-PCR) to detect Ghsr mRNA in the CeA and performed electrophysiological recordings to measure ghrelin effects on GABA transmission in this brain region. Furthermore, we examined whether acute or chronic ethanol treatment would alter these electrophysiological effects. Our qRT-PCR studies show the presence of Ghsr mRNA in the CeA. In naive animals, superfusion of ghrelin increased the amplitude of evoked inhibitory postsynaptic potentials (IPSPs) and the frequency of miniature inhibitory postsynaptic currents (mIPSCs). Coapplication of ethanol further increased the ghrelin-induced enhancement of IPSP amplitude, but to a lesser extent than ethanol alone. When applied alone, ethanol significantly increased IPSP amplitude, but this effect was attenuated by the application of ghrelin. In neurons from chronic ethanol-treated (CET) animals, the magnitude of ghrelin-induced increases in IPSP amplitude was not significantly different from that in naive animals, but the ethanol-induced increase in amplitude was abolished. Superfusion of the GHS-R1A antagonists D-Lys3-GHRP-6 and JMV 3002 decreased evoked IPSP and mIPSC frequency, revealing tonic ghrelin activity in the CeA. D-Lys3-GHRP-6 and JMV 3002 also blocked ghrelin-induced increases in GABAergic responses. Furthermore, D-Lys3-GHRP-6 did not affect ethanol-induced increases in IPSP amplitude. These studies implicate a potential role for the ghrelin system in regulating GABAergic transmission and a complex interaction with ethanol at CeA GABAergic synapses.

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Section: Acute Ethanol Interacts With Ghrelin Effectsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Ghrelin Increases GABAergic Transmission and Interacts with Ethanol Actions in the Rat Central Nucleus of the Amygdala

Cruz

Herman

Cote

et al. 2012

Neuropsychopharmacol

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“…Potentiation of GABA release onto cerebellar Purkinje neurons is eliminated in the presence of AC and protein kinase A (PKA) inhibitors (Kelm et al 2008), and is also affected by compounds targeting phospholipase C and PKC (Kelm et al 2010). The potentiating effect of EtOH is impaired in central amygdala (CeA) in mice that lack PKCε (Bajo et al 2008). Thus, PKC is implicated in both the pre and postsynaptic effects of EtOH at GABAergic synapses.…”

Section: Presynaptic Effects Of Ethanolmentioning

confidence: 99%

“…Acute EtOH augments evoked GABA A receptor-mediated inhibitory postsynaptic currents (IPSCs) by increasing GABA release in both mouse (Bajo et al 2008;Nie et al 2004) and rat CeA neurons (Roberto et al 2003(Roberto et al , 2004.…”

Section: Corticotropin-releasing Factormentioning

confidence: 99%

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Synaptic Effects Induced by Alcohol

Lovinger

Roberto

2010

Current Topics in Behavioral Neurosciences

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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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Protein kinase Cɛ activity regulates mGluR5 surface expression in the rat nucleus accumbens

Schwendt

2016

J of Neuroscience Research

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Type 5 metabotropic glutamate receptors (mGluR5) activate protein kinase C (PKC) via coupling to Gαq/11 protein signaling. We have previously demonstrated that the epsilon isoform of PKC (PKCε) is a critical downstream target of mGluR5 in regulating behavioral and biochemical responses to alcohol. Recent evidence suggests that PKC-mediated phosphorylation of mGluR5 can lead to receptor desensitization and internalization. We therefore sought to examine the specific involvement of PKCε in the regulation of mGluR5 surface expression in the nucleus accumbens (NAc), a key regulator of alcohol-associated behaviors. Coronal brain sections from male Wistar rats analyzed for either co-localization of mGluR5 and PKCε via immunohistochemistry, or changes in mGluR5 surface expression and PKCε phosphorylation following local application of PKCε translocation activator or inhibitor peptides and/or an orthosteric mGluR5 agonist. We observed co-localization of mGluR5 and PKCε in the NAc. We also showed that intra-NAc infusion of PKCε translocation inhibitor εV1-2 increased mGluR5 surface expression under baseline conditions. Stimulation of mGluR5 with an orthosteric agonist DHPG, dose-dependently increased ERK1/2 and PKCε phosphorylation as well as mGluR5 internalization in acute NAc slices. Finally, we observed that activation of PKCε translocation with Tat-ψεRACK peptide mediates agonist-independent mGluR5 internalization, while PKCε translocation inhibitor εV1-2 prevents agonist-dependent internalization of mGluR5 in NAc slice preparations. These findings suggest that the subcellular localization of mGluR5 in the NAc is regulated by PKCε under basal and stimulation conditions, which may influence the role of mGluR5-PKCε signaling in alcohol-related behaviors.

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Protein kinase C epsilon mediation of CRF- and ethanol-induced GABA release in central amygdala

Cited by 112 publications

References 42 publications

Ghrelin Increases GABAergic Transmission and Interacts with Ethanol Actions in the Rat Central Nucleus of the Amygdala

Ghrelin Increases GABAergic Transmission and Interacts with Ethanol Actions in the Rat Central Nucleus of the Amygdala

Synaptic Effects Induced by Alcohol

Protein kinase Cɛ activity regulates mGluR5 surface expression in the rat nucleus accumbens

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