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

Neurobiol Stress. 2023 Jun 4:25:100547. doi: 10.1016/j.ynstr.2023.100547. eCollection 2023 Jul.

Authors

Sophia Khom^{1

2}, Vittoria Borgonetti¹, Valentina Vozella¹, Dean Kirson^{1

3}, Larry Rodriguez¹, Pauravi Gandhi¹, Paula Cristina Bianchi^{1

4}, Angela Snyder¹, Roman Vlkolinsky¹, Michal Bajo¹, Christopher S Oleata¹, Roberto Ciccocioppo⁵, Marisa Roberto^{1

6}

Affiliations

¹ Department of Molecular Medicine, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, CA 92037, USA.
² Department of Pharmaceutical Sciences, University of Vienna, Josef-Holaubek-Platz 2, Vienna, A 1090, Austria.
³ Department of Pharmacology, Addiction Science, and Toxicology, The University of Tennessee Health Science Center, Memphis, TN 38163, USA.
⁴ Department of Pharmacology, Universidade Federal de São Paulo (UNIFESP), São Paulo, SP 04024-002, Brazil.
⁵ School of Pharmacy, Center of Neuroscience, University of Camerino, Italy.
⁶ Department of Neuroscience, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, CA 92037, USA.

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.

Abstract

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