Glucocorticoid receptors regulate central amygdala GABAergic synapses in Marchigian-Sardinian alcohol-preferring rats

Sophia Khom; Vittoria Borgonetti; Valentina Vozella; Dean Kirson; Larry Rodriguez; Pauravi Gandhi; Paula Cristina Bianchi; Angela Snyder; Roman Vlkolinsky; Michal Bajo; Christopher S. Oleata; Roberto Ciccocioppo; Marisa Roberto

doi:10.1016/j.ynstr.2023.100547

Glucocorticoid receptors regulate central amygdala GABAergic synapses in Marchigian-Sardinian alcohol-preferring rats

Sophia Khom
, Vittoria Borgonetti
, Valentina Vozella
, Dean Kirson
, Larry Rodriguez
, Pauravi Gandhi
, Paula Cristina Bianchi
, Angela Snyder
, Roman Vlkolinsky
, Michal Bajo
, Christopher S. Oleata
, Roberto Ciccocioppo
, Marisa Roberto

Department of Pharmaceutical Sciences

Publications: Contribution to journal › Article › Peer Reviewed

Abstract

Impairments in the function of the hypothalamic-pituitary-adrenal (HPA) axis and enhanced glucocorticoid receptor (GR) activity in the central amygdala (CeA) are critical mechanisms in the pathogenesis of alcohol use disorder (AUD). The GR antagonist mifepristone attenuates craving in AUD patients, alcohol consumption in AUD models, and decreases CeA γ-aminobutyric acid (GABA) transmission in alcohol-dependent rats. Previous studies suggest elevated GR activity in the CeA of male alcohol-preferring Marchigian-Sardinian (msP) rats, but its contribution to heightened CeA GABA transmission driving their characteristic post-dependent phenotype is largely unknown. We determined Nr3c1 (the gene encoding GR) gene transcription in the CeA in male and female msP and Wistar rats using in situ hybridization and studied acute effects of mifepristone (10 μM) and its interaction with ethanol (44 mM) on pharmacologically isolated spontaneous inhibitory postsynaptic currents (sIPSCs) and electrically evoked inhibitory postsynaptic potentials (eIPSPs) in the CeA using ex vivo slice electrophysiology. Female rats of both genotypes expressed more CeA GRs than males, suggesting a sexually dimorphic GR regulation of CeA activity. Mifepristone reduced sIPSC frequencies (GABA release) and eIPSP amplitudes in msP rats of both sexes, but not in their Wistar counterparts; however, it did not prevent acute ethanol-induced increase in CeA GABA transmission in male rats. In msP rats, GR regulates CeA GABAergic signaling under basal conditions, indicative of intrinsically active GR. Thus, enhanced GR function in the CeA represents a key mechanism contributing to maladaptive behaviors associated with AUD.

Original language	English
Article number	100547
Journal	Neurobiology of Stress
Volume	25
DOIs	https://doi.org/10.1016/j.ynstr.2023.100547
Publication status	Published - Jul 2023

Funding

This is manuscript number 30222 from The Scripps Research Institute. This study was supported by National Institutes of Health grants AA017447 (MR and RC), AA013498 (MR), AA027700 (MR), AA021491 (MR), AA006420 (MR), AA029841 (MR), AA007456 (MR) and AA026638 (DK), The Schimmel Family Chair, The Pearson Center for Alcoholism Addiction Research and a FAPESP postdoctoral fellowship 2021/12978-1 (PCB). The authors thank Dr. Sarah Wolfe and Shannon D'Ambrosio for technical assistance with the ISH analysis and Michael Arends for editing the manuscript. The authors declare no competing financial interests.

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Austrian Fields of Science 2012

301406 Neuropharmacology
301407 Neurophysiology
301206 Pharmacology

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https://phaidra.univie.ac.at/o:2064280Licence: CC BY-NC-ND 4.0

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Khom, S., Borgonetti, V., Vozella, V., Kirson, D., Rodriguez, L., Gandhi, P., Bianchi, P. C., Snyder, A., Vlkolinsky, R., Bajo, M., Oleata, C. S., Ciccocioppo, R., & Roberto, M. (2023). Glucocorticoid receptors regulate central amygdala GABAergic synapses in Marchigian-Sardinian alcohol-preferring rats. Neurobiology of Stress, 25, Article 100547. https://doi.org/10.1016/j.ynstr.2023.100547

@article{0ab437de51c14c82b0e55b1550f40cca,

title = "Glucocorticoid receptors regulate central amygdala GABAergic synapses in Marchigian-Sardinian alcohol-preferring rats",

abstract = "Impairments in the function of the hypothalamic-pituitary-adrenal (HPA) axis and enhanced glucocorticoid receptor (GR) activity in the central amygdala (CeA) are critical mechanisms in the pathogenesis of alcohol use disorder (AUD). The GR antagonist mifepristone attenuates craving in AUD patients, alcohol consumption in AUD models, and decreases CeA γ-aminobutyric acid (GABA) transmission in alcohol-dependent rats. Previous studies suggest elevated GR activity in the CeA of male alcohol-preferring Marchigian-Sardinian (msP) rats, but its contribution to heightened CeA GABA transmission driving their characteristic post-dependent phenotype is largely unknown. We determined Nr3c1 (the gene encoding GR) gene transcription in the CeA in male and female msP and Wistar rats using in situ hybridization and studied acute effects of mifepristone (10 μM) and its interaction with ethanol (44 mM) on pharmacologically isolated spontaneous inhibitory postsynaptic currents (sIPSCs) and electrically evoked inhibitory postsynaptic potentials (eIPSPs) in the CeA using ex vivo slice electrophysiology. Female rats of both genotypes expressed more CeA GRs than males, suggesting a sexually dimorphic GR regulation of CeA activity. Mifepristone reduced sIPSC frequencies (GABA release) and eIPSP amplitudes in msP rats of both sexes, but not in their Wistar counterparts; however, it did not prevent acute ethanol-induced increase in CeA GABA transmission in male rats. In msP rats, GR regulates CeA GABAergic signaling under basal conditions, indicative of intrinsically active GR. Thus, enhanced GR function in the CeA represents a key mechanism contributing to maladaptive behaviors associated with AUD.",

author = "Sophia Khom and Vittoria Borgonetti and Valentina Vozella and Dean Kirson and Larry Rodriguez and Pauravi Gandhi and Bianchi, \{Paula Cristina\} and Angela Snyder and Roman Vlkolinsky and Michal Bajo and Oleata, \{Christopher S.\} and Roberto Ciccocioppo and Marisa Roberto",

note = "Funding Information: This is manuscript number 30222 from The Scripps Research Institute. This study was supported by National Institutes of Health grants AA017447 (MR and RC), AA013498 (MR), AA027700 (MR), AA021491 (MR), AA006420 (MR), AA029841 (MR), AA007456 (MR) and AA026638 (DK), The Schimmel Family Chair, The Pearson Center for Alcoholism Addiction Research and a FAPESP postdoctoral fellowship 2021/12978-1 (PCB). The authors thank Dr. Sarah Wolfe and Shannon D'Ambrosio for technical assistance with the ISH analysis and Michael Arends for editing the manuscript. The authors declare no competing financial interests. Publisher Copyright: {\textcopyright} 2023",

year = "2023",

month = jul,

doi = "10.1016/j.ynstr.2023.100547",

language = "English",

volume = "25",

journal = "Neurobiology of Stress",

issn = "2352-2895",

publisher = "Elsevier",

}

Khom, S, Borgonetti, V, Vozella, V, Kirson, D, Rodriguez, L, Gandhi, P, Bianchi, PC, Snyder, A, Vlkolinsky, R, Bajo, M, Oleata, CS, Ciccocioppo, R & Roberto, M 2023, 'Glucocorticoid receptors regulate central amygdala GABAergic synapses in Marchigian-Sardinian alcohol-preferring rats', Neurobiology of Stress, vol. 25, 100547. https://doi.org/10.1016/j.ynstr.2023.100547

TY - JOUR

T1 - Glucocorticoid receptors regulate central amygdala GABAergic synapses in Marchigian-Sardinian alcohol-preferring rats

AU - Khom, Sophia

AU - Borgonetti, Vittoria

AU - Vozella, Valentina

AU - Kirson, Dean

AU - Rodriguez, Larry

AU - Gandhi, Pauravi

AU - Bianchi, Paula Cristina

AU - Snyder, Angela

AU - Vlkolinsky, Roman

AU - Bajo, Michal

AU - Oleata, Christopher S.

AU - Ciccocioppo, Roberto

AU - Roberto, Marisa

N1 - Funding Information: This is manuscript number 30222 from The Scripps Research Institute. This study was supported by National Institutes of Health grants AA017447 (MR and RC), AA013498 (MR), AA027700 (MR), AA021491 (MR), AA006420 (MR), AA029841 (MR), AA007456 (MR) and AA026638 (DK), The Schimmel Family Chair, The Pearson Center for Alcoholism Addiction Research and a FAPESP postdoctoral fellowship 2021/12978-1 (PCB). The authors thank Dr. Sarah Wolfe and Shannon D'Ambrosio for technical assistance with the ISH analysis and Michael Arends for editing the manuscript. The authors declare no competing financial interests. Publisher Copyright: © 2023

PY - 2023/7

Y1 - 2023/7

N2 - Impairments in the function of the hypothalamic-pituitary-adrenal (HPA) axis and enhanced glucocorticoid receptor (GR) activity in the central amygdala (CeA) are critical mechanisms in the pathogenesis of alcohol use disorder (AUD). The GR antagonist mifepristone attenuates craving in AUD patients, alcohol consumption in AUD models, and decreases CeA γ-aminobutyric acid (GABA) transmission in alcohol-dependent rats. Previous studies suggest elevated GR activity in the CeA of male alcohol-preferring Marchigian-Sardinian (msP) rats, but its contribution to heightened CeA GABA transmission driving their characteristic post-dependent phenotype is largely unknown. We determined Nr3c1 (the gene encoding GR) gene transcription in the CeA in male and female msP and Wistar rats using in situ hybridization and studied acute effects of mifepristone (10 μM) and its interaction with ethanol (44 mM) on pharmacologically isolated spontaneous inhibitory postsynaptic currents (sIPSCs) and electrically evoked inhibitory postsynaptic potentials (eIPSPs) in the CeA using ex vivo slice electrophysiology. Female rats of both genotypes expressed more CeA GRs than males, suggesting a sexually dimorphic GR regulation of CeA activity. Mifepristone reduced sIPSC frequencies (GABA release) and eIPSP amplitudes in msP rats of both sexes, but not in their Wistar counterparts; however, it did not prevent acute ethanol-induced increase in CeA GABA transmission in male rats. In msP rats, GR regulates CeA GABAergic signaling under basal conditions, indicative of intrinsically active GR. Thus, enhanced GR function in the CeA represents a key mechanism contributing to maladaptive behaviors associated with AUD.

AB - Impairments in the function of the hypothalamic-pituitary-adrenal (HPA) axis and enhanced glucocorticoid receptor (GR) activity in the central amygdala (CeA) are critical mechanisms in the pathogenesis of alcohol use disorder (AUD). The GR antagonist mifepristone attenuates craving in AUD patients, alcohol consumption in AUD models, and decreases CeA γ-aminobutyric acid (GABA) transmission in alcohol-dependent rats. Previous studies suggest elevated GR activity in the CeA of male alcohol-preferring Marchigian-Sardinian (msP) rats, but its contribution to heightened CeA GABA transmission driving their characteristic post-dependent phenotype is largely unknown. We determined Nr3c1 (the gene encoding GR) gene transcription in the CeA in male and female msP and Wistar rats using in situ hybridization and studied acute effects of mifepristone (10 μM) and its interaction with ethanol (44 mM) on pharmacologically isolated spontaneous inhibitory postsynaptic currents (sIPSCs) and electrically evoked inhibitory postsynaptic potentials (eIPSPs) in the CeA using ex vivo slice electrophysiology. Female rats of both genotypes expressed more CeA GRs than males, suggesting a sexually dimorphic GR regulation of CeA activity. Mifepristone reduced sIPSC frequencies (GABA release) and eIPSP amplitudes in msP rats of both sexes, but not in their Wistar counterparts; however, it did not prevent acute ethanol-induced increase in CeA GABA transmission in male rats. In msP rats, GR regulates CeA GABAergic signaling under basal conditions, indicative of intrinsically active GR. Thus, enhanced GR function in the CeA represents a key mechanism contributing to maladaptive behaviors associated with AUD.

UR - https://www.scopus.com/pages/publications/85161294656

U2 - 10.1016/j.ynstr.2023.100547

DO - 10.1016/j.ynstr.2023.100547

M3 - Article

AN - SCOPUS:85161294656

SN - 2352-2895

VL - 25

JO - Neurobiology of Stress

JF - Neurobiology of Stress

M1 - 100547

ER -

Glucocorticoid receptors regulate central amygdala GABAergic synapses in Marchigian-Sardinian alcohol-preferring rats

Abstract

Funding

UN SDGs

Austrian Fields of Science 2012

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