Synaptic adaptations in the central amygdala and hypothalamic paraventricular nucleus associated with protracted ethanol abstinence in male rhesus monkeys

Jimenez, V. A.; Herman, M. A.; Cuzon Carlson, V. C.; Walter, N. A.; Grant, K. A.; Roberto, M.

doi:10.1038/s41386-018-0290-7

Cited by 29Neuroscience and Neuropharmacology ResearchNeurotransmitter Receptor Influence on BehaviorStress Responses and Cortisol

Synaptic adaptations in the central amygdala and hypothalamic paraventricular nucleus associated with protracted ethanol abstinence in male rhesus monkeys

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Jimenez, V. A., Herman, M. A., Cuzon Carlson, V. C., Walter, N. A., Grant, K. A., Roberto, M.·2019·Neuropsychopharmacology

DOI 10.1038/s41386-018-0290-7PMC PMC6461779

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Abstract

Alcohol use disorder is a significant global burden. Stress has been identified as an etiological factor in the initiation and continuation of ethanol consumption. Understanding adaptations within stress circuitry is an important step toward novel treatment strategies. The effects of protracted abstinence following long-term ethanol self-administration on the central nucleus of the amygdala (CeA) and the hypothalamic paraventricular nucleus (PVN) were evaluated in male rhesus monkeys. Using whole-cell patch-clamp electrophysiology, inhibitory GABAergic transmission in the CeA and excitatory glutamatergic transmission in the PVN were measured. CeA neurons from abstinent drinkers displayed an elevated baseline spontaneous inhibitory postsynaptic current (sIPSC) frequency compared with controls, indicating increased presynaptic GABA release. Application of acute ethanol significantly increased the frequency of sIPSCs in controls, but not in abstinent drinkers, suggesting a tolerance to ethanol-enhanced GABA release in abstinent rhesus monkeys with a history of chronic ethanol self-administration and repeated abstinence. In the PVN, the frequency of spontaneous excitatory postsynaptic currents (sEPSC) was elevated in abstinent drinkers compared with controls, indicating increased presynaptic glutamate release. Notably, acute ethanol decreased presynaptic glutamate release onto parvocellular PVN neurons in both controls and abstinent drinkers, suggesting a lack of tolerance to acute ethanol among PVN neurons. These results are the first to demonstrate distinct synaptic adaptations and ethanol sensitivity in both the extrahypothalamic and hypothalamic stress circuits in abstinent rhesus males. Importantly, our findings describe adaptations in stress circuitry present in the brain at a state during abstinence, just prior to relapse to ethanol drinking.

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Elevated GABAergic signaling in the CeA following chronic alcohol exposure is observed across multiple species.
“Elevated GABAergic signaling in the CeA following chronic alcohol exposure is observed across multiple species (28, 33, 108, 109), and reducing the heightened GABAergic tone in the CeA is a common denominator of various drugs that suppress alcohol consumption (101, 110, 111).”
From The glucagon-like peptide-1 (GLP-1) analogue semaglutide reduces alcohol drinking and modulates central GABA neurotransmission (2023) · cites this paper as [109]
Alcohol heightens CeA GABA transmission across species.
“alcohol heightens CeA GABA transmission (Augier et al., 2018;Herman et al., 2016;Jimenez et al., 2019;Kirson et al., 2021;Roberto et al., 2004;Roberto et al., 2003).”
From Alcohol dependence and withdrawal increase sensitivity of central amygdalar GABAergic synapses to the glucocorticoid receptor antagonist mifepristone in male rats (2022) · cites this paper as Jimenez et al., 2019
Heightened CeA GABAergic signaling is a hallmark of excessive drinking and a key mechanism of alcohol-dependence associated behaviors across species.
“Heightened CeA GABAergic signaling is a hallmark of excessive drinking and a key mechanism of alcohol-dependence associated behaviors across species (Augier et al., 2018;Herman et al., 2016;Jimenez et al., 2019;Roberto et al., 2004).”
From Alcohol dependence and withdrawal increase sensitivity of central amygdalar GABAergic synapses to the glucocorticoid receptor antagonist mifepristone in male rats (2022) · cites this paper as Jimenez et al., 2019

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Authors: Jimenez, V. A., Herman, M. A., Cuzon Carlson, V. C., Walter, N. A., Grant, K. A., & Roberto, M.
Affiliations: Oregon National Primate Research Center (US)
University of North Carolina at Chapel Hill (US)
Scripps Research Institute (US)
ORCID: Herman, M. A.
Walter, N. A.
Grant, K. A.
Roberto, M.
Venue: Neuropsychopharmacology
Publisher: Springer Science and Business Media LLC
Published: 2018-12-05
Volume: 44
Issue: 5
Pages: 982-993
ISSN: 0893-133X (ISSN-L)
1740-634X
DOI: 10.1038/s41386-018-0290-7
PMC: PMC6461779
OpenAlex: W2903342168
Cited by: 29
References: 65
Citations by year: 2026: 2 · 2025: 5 · 2023: 6 · 2022: 2 · 2021: 5 · 2020: 8 · 2019: 1
FWCI: 1.59
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: other-oa
www.springer.com/tdm (tdm)
www.springer.com/tdm (vor)
Locations: Neuropsychopharmacology (publishedVersion, other-oa)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: U.S. Department of Health & Human Services | NIH | National Institute on Alcohol Abuse and Alcoholism (AA019431, AA013641, AA013510, AA013498, AA006420, AA15566)
Topics: Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
Keywords: alcohol abstinence, central amygdala, hypothalamic paraventricular nucleus, synaptic plasticity, GABAergic neurotransmission, glutamatergic neurotransmission, ethanol tolerance, ethanol sensitivity, alcoholism, rhesus monkeys, relapse, presynaptic neurotransmitter release
MeSH terms: Adaptation, Physiological, Ethanol, Alcoholism, Animals, Central Nervous System Depressants, Disease Models, Animal, Drug Tolerance, gamma-Aminobutyric Acid, Macaca mulatta, Male, Paraventricular Hypothalamic Nucleus, Patch-Clamp Techniques, Glutamic Acid, Excitatory Postsynaptic Potentials, Inhibitory Postsynaptic Potentials, Alcohol Abstinence, Central Amygdaloid Nucleus

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Synaptic adaptations in the central amygdala and hypothalamic paraventricular nucleus associated with protracted ethanol abstinence in male rhesus monkeys

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