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Ethanol produces corticotropin-releasing factor receptor-dependent enhancement of spontaneous glutamatergic transmission in the mouse central amygdala.
Alcohol Clin Exp Res 2015; 39(11):2154-62AC

Abstract

BACKGROUND

Ethanol (EtOH) modulation of central amygdala (CeA) neurocircuitry plays a key role in the development of alcoholism via activation of the corticotropin-releasing factor (CRF) receptor (CRFR) system. Previous work has predominantly focused on EtOH × CRF interactions on the CeA GABA circuitry; however, our laboratory recently showed that CRF enhances CeA glutamatergic transmission. Therefore, this study sought to determine whether EtOH modulates CeA glutamate transmission via activation of CRF signaling.

METHODS

The effects of EtOH on spontaneous excitatory postsynaptic currents (sEPSCs) and basal resting membrane potentials were examined via standard electrophysiology methods in adult male C57BL/6J mice. Local ablation of CeA CRF neurons (CRF(CeAhDTR)) was achieved by targeting the human diphtheria toxin receptor (hDTR) to CeA CRF neurons with an adeno-associated virus. Ablation was quantified post hoc with confocal microscopy. Genetic targeting of the diphtheria toxin active subunit to CRF neurons (CRF(DTA) mice) ablated CRF neurons throughout the central nervous system, as assessed by quantitative reverse transcriptase polymerase chain reaction quantification of CRF mRNA.

RESULTS

Acute bath application of EtOH significantly increased sEPSC frequency in a concentration-dependent manner in CeA neurons, and this effect was blocked by pretreatment of co-applied CRFR1 and CRFR2 antagonists. In experiments utilizing a CRF-tomato reporter mouse, EtOH did not significantly alter the basal membrane potential of CeA CRF neurons. The ability of EtOH to enhance CeA sEPSC frequency was not altered in CRF(CeAhDTR) mice despite a ~78% reduction in CeA CRF cell counts. The ability of EtOH to enhance CeA sEPSC frequency was also not altered in the CRF(DTA) mice despite a 3-fold reduction in CRF mRNA levels.

CONCLUSIONS

These findings demonstrate that EtOH enhances spontaneous glutamatergic transmission in the CeA via a CRFR-dependent mechanism. Surprisingly, our data suggest that this action may not require endogenous CRF.

Authors+Show Affiliations

Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee.Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee. Vanderbilt Brain Institute, Vanderbilt University School of Medicine, Nashville, Tennessee.Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee.Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee.Section on Fundamental Neuroscience, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland.Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee. Vanderbilt Brain Institute, Vanderbilt University School of Medicine, Nashville, Tennessee.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

26503065

Citation

Silberman, Yuval, et al. "Ethanol Produces Corticotropin-releasing Factor Receptor-dependent Enhancement of Spontaneous Glutamatergic Transmission in the Mouse Central Amygdala." Alcoholism, Clinical and Experimental Research, vol. 39, no. 11, 2015, pp. 2154-62.
Silberman Y, Fetterly TL, Awad EK, et al. Ethanol produces corticotropin-releasing factor receptor-dependent enhancement of spontaneous glutamatergic transmission in the mouse central amygdala. Alcohol Clin Exp Res. 2015;39(11):2154-62.
Silberman, Y., Fetterly, T. L., Awad, E. K., Milano, E. J., Usdin, T. B., & Winder, D. G. (2015). Ethanol produces corticotropin-releasing factor receptor-dependent enhancement of spontaneous glutamatergic transmission in the mouse central amygdala. Alcoholism, Clinical and Experimental Research, 39(11), pp. 2154-62. doi:10.1111/acer.12881.
Silberman Y, et al. Ethanol Produces Corticotropin-releasing Factor Receptor-dependent Enhancement of Spontaneous Glutamatergic Transmission in the Mouse Central Amygdala. Alcohol Clin Exp Res. 2015;39(11):2154-62. PubMed PMID: 26503065.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Ethanol produces corticotropin-releasing factor receptor-dependent enhancement of spontaneous glutamatergic transmission in the mouse central amygdala. AU - Silberman,Yuval, AU - Fetterly,Tracy L, AU - Awad,Elias K, AU - Milano,Elana J, AU - Usdin,Ted B, AU - Winder,Danny G, Y1 - 2015/10/07/ PY - 2015/02/11/received PY - 2015/08/14/accepted PY - 2015/10/28/entrez PY - 2015/10/28/pubmed PY - 2016/8/19/medline KW - CRF Reporter Mice KW - Central Nucleus of the Amygdala KW - Diphtheria Toxin KW - Selective Deletion KW - Whole-Cell Patch-Clamp Electrophysiology SP - 2154 EP - 62 JF - Alcoholism, clinical and experimental research JO - Alcohol. Clin. Exp. Res. VL - 39 IS - 11 N2 - BACKGROUND: Ethanol (EtOH) modulation of central amygdala (CeA) neurocircuitry plays a key role in the development of alcoholism via activation of the corticotropin-releasing factor (CRF) receptor (CRFR) system. Previous work has predominantly focused on EtOH × CRF interactions on the CeA GABA circuitry; however, our laboratory recently showed that CRF enhances CeA glutamatergic transmission. Therefore, this study sought to determine whether EtOH modulates CeA glutamate transmission via activation of CRF signaling. METHODS: The effects of EtOH on spontaneous excitatory postsynaptic currents (sEPSCs) and basal resting membrane potentials were examined via standard electrophysiology methods in adult male C57BL/6J mice. Local ablation of CeA CRF neurons (CRF(CeAhDTR)) was achieved by targeting the human diphtheria toxin receptor (hDTR) to CeA CRF neurons with an adeno-associated virus. Ablation was quantified post hoc with confocal microscopy. Genetic targeting of the diphtheria toxin active subunit to CRF neurons (CRF(DTA) mice) ablated CRF neurons throughout the central nervous system, as assessed by quantitative reverse transcriptase polymerase chain reaction quantification of CRF mRNA. RESULTS: Acute bath application of EtOH significantly increased sEPSC frequency in a concentration-dependent manner in CeA neurons, and this effect was blocked by pretreatment of co-applied CRFR1 and CRFR2 antagonists. In experiments utilizing a CRF-tomato reporter mouse, EtOH did not significantly alter the basal membrane potential of CeA CRF neurons. The ability of EtOH to enhance CeA sEPSC frequency was not altered in CRF(CeAhDTR) mice despite a ~78% reduction in CeA CRF cell counts. The ability of EtOH to enhance CeA sEPSC frequency was also not altered in the CRF(DTA) mice despite a 3-fold reduction in CRF mRNA levels. CONCLUSIONS: These findings demonstrate that EtOH enhances spontaneous glutamatergic transmission in the CeA via a CRFR-dependent mechanism. Surprisingly, our data suggest that this action may not require endogenous CRF. SN - 1530-0277 UR - https://www.unboundmedicine.com/medline/citation/26503065/Ethanol_produces_corticotropin_releasing_factor_receptor_dependent_enhancement_of_spontaneous_glutamatergic_transmission_in_the_mouse_central_amygdala_ L2 - https://doi.org/10.1111/acer.12881 DB - PRIME DP - Unbound Medicine ER -