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A Functional Switch in Tonic GABA Currents Alters the Output of Central Amygdala Corticotropin Releasing Factor Receptor-1 Neurons Following Chronic Ethanol Exposure.
J Neurosci. 2016 10 19; 36(42):10729-10741.JN

Abstract

The corticotropin releasing factor (CRF) system in the central amygdala (CeA) has been implicated in the effects of acute ethanol and the development of alcohol dependence. We previously demonstrated that CRF receptor 1 (CRF1) neurons comprise a specific component of the CeA microcircuitry that is selectively engaged by acute ethanol. To investigate the impact of chronic ethanol exposure on inhibitory signaling in CRF1+ CeA neurons, we used CRF1:GFP mice subjected to chronic intermittent ethanol (CIE) inhalation and examined changes in local inhibitory control, the effects of acute ethanol, and the output of these neurons from the CeA. Following CIE, CRF1+ neurons displayed decreased phasic inhibition and a complete loss of tonic inhibition that persisted into withdrawal. CRF1- neurons showed a cell type-specific upregulation of both phasic and tonic signaling with CIE, the latter of which persists into withdrawal and is likely mediated by δ subunit-containing GABAA receptors. The loss of tonic inhibition with CIE was seen in CRF1+ and CRF1- neurons that project out of the CeA and into the bed nucleus of the stria terminalis. CRF1+ projection neurons displayed an increased baseline firing rate and loss of sensitivity to acute ethanol following CIE. These data demonstrate that chronic ethanol exposure produces profound and long-lasting changes in local inhibitory control of the CeA, resulting in an increase in the output of the CeA and the CRF1 receptor system, in particular. These cellular changes could underlie the behavioral manifestations of alcohol dependence and potentially contribute to the pathology of addiction.

SIGNIFICANCE STATEMENT

The corticotropin releasing factor (CRF) system in the central amygdala (CeA) has been implicated in the effects of acute and chronic ethanol. We showed previously that CRF receptor 1-expressing (CRF1+) neurons in the CeA are under tonic inhibitory control and are differentially regulated by acute ethanol (Herman et al., 2013). Here we show that the inhibitory control of CRF1+ CeA neurons is lost with chronic ethanol exposure, likely by a functional switch in local tonic signaling. The loss of tonic inhibition is seen in CRF1+ projection neurons, suggesting that a critical consequence of chronic ethanol exposure is an increase in the output of the CeA CRF1 system, a neuroadaptation that may contribute to the behavioral consequences of alcohol dependence.

Authors+Show Affiliations

Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, California 92037 mherman@scripps.edu.Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, California 92037.Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, California 92037.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

27798128

Citation

Herman, Melissa A., et al. "A Functional Switch in Tonic GABA Currents Alters the Output of Central Amygdala Corticotropin Releasing Factor Receptor-1 Neurons Following Chronic Ethanol Exposure." The Journal of Neuroscience : the Official Journal of the Society for Neuroscience, vol. 36, no. 42, 2016, pp. 10729-10741.
Herman MA, Contet C, Roberto M. A Functional Switch in Tonic GABA Currents Alters the Output of Central Amygdala Corticotropin Releasing Factor Receptor-1 Neurons Following Chronic Ethanol Exposure. J Neurosci. 2016;36(42):10729-10741.
Herman, M. A., Contet, C., & Roberto, M. (2016). A Functional Switch in Tonic GABA Currents Alters the Output of Central Amygdala Corticotropin Releasing Factor Receptor-1 Neurons Following Chronic Ethanol Exposure. The Journal of Neuroscience : the Official Journal of the Society for Neuroscience, 36(42), 10729-10741.
Herman MA, Contet C, Roberto M. A Functional Switch in Tonic GABA Currents Alters the Output of Central Amygdala Corticotropin Releasing Factor Receptor-1 Neurons Following Chronic Ethanol Exposure. J Neurosci. 2016 10 19;36(42):10729-10741. PubMed PMID: 27798128.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - A Functional Switch in Tonic GABA Currents Alters the Output of Central Amygdala Corticotropin Releasing Factor Receptor-1 Neurons Following Chronic Ethanol Exposure. AU - Herman,Melissa A, AU - Contet,Candice, AU - Roberto,Marisa, PY - 2016/04/15/received PY - 2016/08/10/accepted PY - 2016/11/1/pubmed PY - 2017/7/25/medline PY - 2016/11/1/entrez KW - CRF KW - CRF1 KW - GABA KW - alcohol KW - amygdala KW - tonic SP - 10729 EP - 10741 JF - The Journal of neuroscience : the official journal of the Society for Neuroscience JO - J Neurosci VL - 36 IS - 42 N2 - : The corticotropin releasing factor (CRF) system in the central amygdala (CeA) has been implicated in the effects of acute ethanol and the development of alcohol dependence. We previously demonstrated that CRF receptor 1 (CRF1) neurons comprise a specific component of the CeA microcircuitry that is selectively engaged by acute ethanol. To investigate the impact of chronic ethanol exposure on inhibitory signaling in CRF1+ CeA neurons, we used CRF1:GFP mice subjected to chronic intermittent ethanol (CIE) inhalation and examined changes in local inhibitory control, the effects of acute ethanol, and the output of these neurons from the CeA. Following CIE, CRF1+ neurons displayed decreased phasic inhibition and a complete loss of tonic inhibition that persisted into withdrawal. CRF1- neurons showed a cell type-specific upregulation of both phasic and tonic signaling with CIE, the latter of which persists into withdrawal and is likely mediated by δ subunit-containing GABAA receptors. The loss of tonic inhibition with CIE was seen in CRF1+ and CRF1- neurons that project out of the CeA and into the bed nucleus of the stria terminalis. CRF1+ projection neurons displayed an increased baseline firing rate and loss of sensitivity to acute ethanol following CIE. These data demonstrate that chronic ethanol exposure produces profound and long-lasting changes in local inhibitory control of the CeA, resulting in an increase in the output of the CeA and the CRF1 receptor system, in particular. These cellular changes could underlie the behavioral manifestations of alcohol dependence and potentially contribute to the pathology of addiction. SIGNIFICANCE STATEMENT: The corticotropin releasing factor (CRF) system in the central amygdala (CeA) has been implicated in the effects of acute and chronic ethanol. We showed previously that CRF receptor 1-expressing (CRF1+) neurons in the CeA are under tonic inhibitory control and are differentially regulated by acute ethanol (Herman et al., 2013). Here we show that the inhibitory control of CRF1+ CeA neurons is lost with chronic ethanol exposure, likely by a functional switch in local tonic signaling. The loss of tonic inhibition is seen in CRF1+ projection neurons, suggesting that a critical consequence of chronic ethanol exposure is an increase in the output of the CeA CRF1 system, a neuroadaptation that may contribute to the behavioral consequences of alcohol dependence. SN - 1529-2401 UR - https://www.unboundmedicine.com/medline/citation/27798128/A_Functional_Switch_in_Tonic_GABA_Currents_Alters_the_Output_of_Central_Amygdala_Corticotropin_Releasing_Factor_Receptor_1_Neurons_Following_Chronic_Ethanol_Exposure_ L2 - http://www.jneurosci.org/cgi/pmidlookup?view=long&pmid=27798128 DB - PRIME DP - Unbound Medicine ER -