Alcohol Dependence and Withdrawal Impair Serotonergic Regulation of GABA Transmission in the Rat Central Nucleus of the Amygdala
Open accessAbstract
Excessive serotonin (5-HT) signaling plays a critical role in the etiology of alcohol use disorder. The central nucleus of the amygdala (CeA) is a key player in alcohol-dependence associated behaviors. The CeA receives dense innervation from the dorsal raphe nucleus, the major source of 5-HT, and expresses 5-HT receptor subtypes (e.g., 5-HT2C and 5-HT1A) critically linked to alcohol use disorder. Notably, the role of 5-HT regulating rat CeA activity in alcohol dependence is poorly investigated. Here, we examined neuroadaptations of CeA 5-HT signaling in adult, male Sprague Dawley rats using an established model of alcohol dependence (chronic intermittent alcohol vapor exposure), ex vivo slice electrophysiology and ISH. 5-HT increased frequency of sIPSCs without affecting postsynaptic measures, suggesting increased CeA GABA release in naive rats. In dependent rats, this 5-HT-induced increase of GABA release was attenuated, suggesting blunted CeA 5-HT sensitivity, which partially recovered in protracted withdrawal (2 weeks). 5-HT increased vesicular GABA release in naive and dependent rats but had split effects (increase and decrease) after protracted withdrawal indicative of neuroadaptations of presynaptic 5-HT receptors. Accordingly, 5-HT abolished spontaneous neuronal firing in naive and dependent rats but had bidirectional effects in withdrawn. Alcohol dependence and protracted withdrawal did not alter either 5-HT1A-mediated decrease of CeA GABA release or Htr1a expression but disrupted 5-HT2C-signaling without affecting Htr2c expression. Collectively, our study provides detailed insights into modulation of CeA activity by the 5-HT system and unravels the vulnerability of the CeA 5-HT system to chronic alcohol and protracted withdrawal. SIGNIFICANCE STATEMENT Elevated GABA signaling in the central nucleus of the amygdala (CeA) underlies key behaviors associated with alcohol dependence. The CeA is reciprocally connected with the dorsal raphe nucleus, the main source of serotonin (5-HT) in the mammalian brain, and excessive 5-HT signaling is critically implicated in the etiology of alcohol use disorder. Our study, using a well-established rat model of alcohol dependence, ex vivo electrophysiology and ISH, provides mechanistic insights into how both chronic alcohol exposure and protracted withdrawal dysregulate 5-HT signaling in the CeA. Thus, our study further expands our understanding of CeA cellular mechanisms involved in the pathophysiology of alcohol dependence and withdrawal.
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GABAergic transmission is elevated in the CeA following both acute and chronic alcohol exposure, representing critical neuroadaptations in the transition to dependence.
“Of note, GABAergic transmission is elevated in the CeA following both acute and chronic alcohol exposure, representing critical neuroadaptations in the transition to dependence (28, 31–33).”
From The glucagon-like peptide-1 (GLP-1) analogue semaglutide reduces alcohol drinking and modulates central GABA neurotransmission (2023) · cites this paper as [31]
The brain slices underwent acute in vitro withdrawal because no ethanol was added to the solutions used for preparation and incubation.
“We did not add ethanol to any of the solutions used for preparation and incubation of brain slices; thus, the slices underwent acute in vitro withdrawal, as previously shown (31, 32, 101).”
From The glucagon-like peptide-1 (GLP-1) analogue semaglutide reduces alcohol drinking and modulates central GABA neurotransmission (2023) · cites this paper as [31]
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“In addition to increasing the content of γ -GABA in the brain, alcohol also affects the release of neurotransmitter 5-HT (Khom et al., 2020; Oubraim et al., 2022).”
BackgroundNoradrenaline Modulates Central Amygdala GABA Transmission and Alcohol Drinking in Female Rats
Anjos-Santos, A., Erikson, C. M., Flores‐Ramirez, F. J., Rodriguez, L., Barchiesi, R., Vozella, V., Borgonetti, V., Cruz, B., Zalfa, C., Hughes, K. J., et al. (2025) · Biological Psychiatry · doi:10.1016/j.biopsych.2025.03.024 · Cited by 11 · see citing works
Self-citationKhom, S., Borgonetti, V., Vozella, V., Kirson, D., Rodriguez, L., Gandhi, P. J., Bianchi, P., Snyder, A. E., Vlkolinský, R., Bajo, M., et al. (2023) · Neurobiology of Stress · doi:10.1016/j.ynstr.2023.100547 · Cited by 12 · see citing works
Self-citationKhom, S., Nguyen, J. D., Vandewater, S. A., Grant, Y., Roberto, M., & Taffe, M. A. (2021) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2021.780500 · Cited by 10 · see citing works
Self-citationRegulation of alcohol drinking by ventral striatum and extended amygdala circuitry
Borrego, M. B., Chan, A. E., & Ozburn, A. R. (2022) · Neuropharmacology · doi:10.1016/j.neuropharm.2022.109074 · Cited by 11 · see citing works
Chapp, A. D., Shan, Z. J., & Chen, Q. (2024) · Antioxidants · doi:10.3390/antiox13020139 · Cited by 11 · see citing works
“Contrary to the abundance of GABAergic inputs on presynaptic glutamatergic inputs to the PVN, presynaptic inputs to the CeA appear as a heterogenous mixture of glutamatergic [194], GABAergic [195], serotonergic [196], and norepinephrinergic [197] projections.”
BackgroundBehavioral and biochemical effects of alcohol withdrawal in female C3H/HeNRj and C57BL/6JRj mice
Tonetto, S., Weikop, P., Brudek, T., & Thomsen, M. (2023) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2023.1143720 · Cited by 9 · see citing works
“Despite extensive evidence on the dysregulation of dopaminergic, noradrenergic, and serotonergic signaling in AUD, we detected no significant changes in the concentrations of NE, DA, 5-HT, HVA, and 5-HIAA in both the striatum and hippocampus of C3H and B6 mice (Fitzgerald, 2013; Marcinkiewcz et al., 2016; Haass-Koffle…”
BackgroundNutritional ketosis as treatment for alcohol withdrawal symptoms in female C57BL/6J mice
Tonetto, S., Weikop, P., & Thomsen, M. (2024) · Scientific Reports · doi:10.1038/s41598-024-55310-3 · Cited by 7 · see citing works
Targeting IL-6 as a novel therapeutic approach for alcohol abstinence – related mechanical allodynia
Borgonetti, V., Onge, C. M. S., Cruz, B., Zalfa, C., Nadav, T., Roberts, A. J., Galeotti, N., Bajo, M., & Roberto, M. (2025) · Neuropharmacology · doi:10.1016/j.neuropharm.2025.110584 · Cited by 8 · see citing works
“RNAscope was performed as reported previously (Agoglia et al., 2020; Borgonetti et al., 2023a; Khom et al., 2020; Wolfe et al., 2019).”
Self-citationZhang, N., Zhang, H., Liang, X., Xu, Y., Wang, G., Bai, Y., Zhou, Z., Pu, Y., Zhou, Y., Xue, M., et al. (2025) · Food & Function · doi:10.1039/d5fo00260e · Cited by 5 · see citing works
Serotonin circuits act cooperatively with pathophysiology of opioid use disorder
Arakawa, H., & Akihiko, O. (2024) · Addiction Neuroscience · doi:10.1016/j.addicn.2024.100187 · Cited by 4 · see citing works
Chapp, A. D., Huber, M. J., Collins, A. R., Driscoll, K. M., Behnke, J. E., Larson, R. A., Shan, Z. J., Zhang, L., & Chen, Q. (2020) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2020.07.20.212597 · Cited by 3 · see citing works
Emerging GPCR targets for AUD: Insights from preclinical studies
Anversa, R. G., Barron, M. L., Walker, L. C., & Lawrence, A. J. (2024) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2024.102896 · Cited by 3 · see citing works
“In contrast, the selective NK1R antagonist L822429 blocked alcohol-induced GABA release in the CeA of alcohol-dependent rats undergoing withdrawal, but had no effect in naı¨ve rats, suggesting that alcohol dependence engages the SP/NK1R system [68].”
BackgroundCastro‐Zavala, A., Boonen, K., Sánchez‐Marín, L., Roberto, M., Pavón, F. J., de Fonseca, F. R., & Serrano, A. (2025) · Neuropharmacology · doi:10.1016/j.neuropharm.2025.110773 · Cited by 1 · see citing works
Self-citationThe effect of alcohol on brain structures involved in the formation of addiction
Chaikovska, V. R., & Pershyn, M. (2024) · Reports of Vinnytsia National Medical University · doi:10.31393/reports-vnmedical-2024-28(3)-27 · Cited by 1 · see citing works
Jiang, J. W., Chang, J., Wang, D., Yang, X., Wenhui, Z., Yao, P., Jiang, Y., Song, K., Chang, S., Zhang, X.-S., et al. (2023) · Research Square · doi:10.21203/rs.3.rs-2774761/v1 · Cited by 1 · see citing works
Khom, S., Nguyen, J. D., Vandewater, S. A., Grant, Y., Roberto, M., & Taffe, M. A. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.09.24.461477
Self-citationHavrylov, O., & Gomon, M. L. (2022) · Reports of Vinnytsia National Medical University · doi:10.31393/reports-vnmedical-2022-26(2)-10
SU-6656 attenuates alcohol dependence induced withdrawal syndrome in mice
Singh, A. P., Sharma, A. K., & Singh, T. G. (2022) · International Journal of Health Sciences · doi:10.53730/ijhs.v6ns4.10662
“Administration of Src PTK inhibitor, PP2, in the dorsal striatum of rats attenuated operant self‐administration of alcohol (Khom et al., 2020).”
BackgroundJiang, J., Wang, D., Jiang, Y., Yang, X., Sun, R., Chang, J., Zhu, W., Yao, P., Song, K., Chang, S., et al. (2024) · Figshare · doi:10.6084/m9.figshare.25506601
George, B. E., Vidrascu, E., Neira, S., Devine, M. P., & Kash, T. L. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.01.30.702832
“…microinfusion of a non-selective 5-HT2 agonist in the basolateral amygdala attenuated alcohol seeking but had only moderate effects on consumption of a sweetened alcohol solution 61 , and alcohol dependence and withdrawal disrupted central amygdala 5-HT2C signaling without altering expression 62 .”
Gashi, L., Lubec, J., Daneyshar, B. H., Steinkellner, T., & Khom, S. (2026) · Neuropharmacology · doi:10.1016/j.neuropharm.2026.110927
Self-citationMoss, E. M., Batsaikhan, E., Amsden, S., & Kirson, D. (2026) · Alcoholism Clinical and Experimental Research · doi:10.1111/acer.70290
Self-citationTranslational evidence for increased central amygdala IL-6 activity in alcohol dependence
Onge, C. M. S., Erikson, C. M., Cruz, B., Borgonetti, V., Hashimoto, J. G., Cucinello‐Ragland, J. A., Fitzpatrick‐Schmidt, T., Rodriguez, L., Khom, S., Palmisano, M., et al. (2026) · Journal of Neuroinflammation · doi:10.1186/s12974-026-03868-2
Self-citationZaniewska, M. (2026) · Pharmacological Reports · doi:10.1007/s43440-026-00860-8
“…TBC): ↓ 5-HT 3 receptor function (NAC) [231 ] ♂SD rats (intermittent alcohol vapor): ↓ 5-HT-induced increase in the sIPSCs frequency (CeA) [243 ] ↓ 5-HT 2C receptor function (CeA) [243 ] Ø 5-HT 1A receptor function, Ø 5-HT 1A, 2C receptor expression (CeA) [243 ] Ø 5-HT-induced increase in…”
InfluentialRitchie, J. L., Eberle, M. R., Roland, A. V., Taxier, L. R., Campeau, M. R., George, B. E., Kooyman, L. S., & Kash, T. L. (2026) · Neuropsychopharmacology · doi:10.1038/s41386-026-02558-0
Marsland, P., Penta, P. T., Towner, T. T., Coleman, H. J., Liss, A., Varlinskaya, E. I., Werner, D. F., & Varodayan, F. P. (2026) · Neuropharmacology · doi:10.1016/j.neuropharm.2026.111203
Self-citationАлкогольный делирий: перспективы патогенетического лечения
Тарасов, А. А., & Григорьева, И. В. (2026) · Психиатрия психотерапия и клиническая психология · doi:10.34883/pi.2026.17.3.025
- Authors
- Khom, S., Wolfe, S. A., Patel, R. R., Kirson, D., Hedges, D. M., Varodayan, F. P., Bajo, M., & Roberto, M.
- Affiliations
- Scripps Research Institute (US)
- ORCID
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2020-08-07
- Volume
- 40
- Issue
- 36
- Pages
- 6842-6853
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC7470924
- OpenAlex
- W3047642950
- Cited by
- 44
- References
- 67
- Citations by year
- 2026: 8 · 2025: 5 · 2024: 11 · 2023: 7 · 2022: 7 · 2021: 5 · 2020: 1
- FWCI
- 2.29
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Neuroscience (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Austrian Science Fund (J 3942, AA015566, AA021491, AA006420)
- National Institutes of Health (AA007456, AA015566, AA006420, AA027700)
- National Institute on Alcohol Abuse and Alcoholism (R01AA021491, R01AA026865, K99AA026638, R00AA025408, F32AA025262, R01AA015566, P50AA006420, R00AA026638, R01AA027700, R01AA017477, K99AA025408, R01AA017447, U01AA013498, T32AA007456, P60AA006420)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Health Sciences › Medicine › Epidemiology › Substance Abuse Treatment and Outcomes
- Keywords
- alcoholism, alcohol withdrawal, central amygdala, serotonin signaling, GABA release, 5-HT2C receptor, 5-HT1A receptor, dorsal raphe nucleus, neural adaptation, spontaneous neuronal firing
- MeSH terms
- Action Potentials, Alcoholism, Animals, gamma-Aminobutyric Acid, Male, Synaptic Transmission, Serotonin, Substance Withdrawal Syndrome, Rats, Sprague-Dawley, Rats, Inhibitory Postsynaptic Potentials, Central Amygdaloid Nucleus
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