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Alcohol Dependence and Withdrawal Impair Serotonergic Regulation of GABA Transmission in the Rat Central Nucleus of the Amygdala.
J Neurosci. 2020 09 02; 40(36):6842-6853.JN

Abstract

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 Accordingly, 5-HT abolished spontaneous neuronal firing in naive and dependent rats but had bidirectional effects in withdrawn.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.

Authors+Show Affiliations

Department of Molecular Medicine, The Scripps Research Institute, La Jolla, California 92307.Department of Molecular Medicine, The Scripps Research Institute, La Jolla, California 92307.Department of Molecular Medicine, The Scripps Research Institute, La Jolla, California 92307.Department of Molecular Medicine, The Scripps Research Institute, La Jolla, California 92307.Department of Molecular Medicine, The Scripps Research Institute, La Jolla, California 92307.Department of Molecular Medicine, The Scripps Research Institute, La Jolla, California 92307.Department of Molecular Medicine, The Scripps Research Institute, La Jolla, California 92307.Department of Molecular Medicine, The Scripps Research Institute, La Jolla, California 92307 mroberto@scripps.edu.

Pub Type(s)

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

Language

eng

PubMed ID

32769108

Citation

Khom, Sophia, et al. "Alcohol Dependence and Withdrawal Impair Serotonergic Regulation of GABA Transmission in the Rat Central Nucleus of the Amygdala." The Journal of Neuroscience : the Official Journal of the Society for Neuroscience, vol. 40, no. 36, 2020, pp. 6842-6853.
Khom S, Wolfe SA, Patel RR, et al. Alcohol Dependence and Withdrawal Impair Serotonergic Regulation of GABA Transmission in the Rat Central Nucleus of the Amygdala. J Neurosci. 2020;40(36):6842-6853.
Khom, S., Wolfe, S. A., Patel, R. R., Kirson, D., Hedges, D. M., Varodayan, F. P., Bajo, M., & Roberto, M. (2020). Alcohol Dependence and Withdrawal Impair Serotonergic Regulation of GABA Transmission in the Rat Central Nucleus of the Amygdala. The Journal of Neuroscience : the Official Journal of the Society for Neuroscience, 40(36), 6842-6853. https://doi.org/10.1523/JNEUROSCI.0733-20.2020
Khom S, et al. Alcohol Dependence and Withdrawal Impair Serotonergic Regulation of GABA Transmission in the Rat Central Nucleus of the Amygdala. J Neurosci. 2020 09 2;40(36):6842-6853. PubMed PMID: 32769108.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Alcohol Dependence and Withdrawal Impair Serotonergic Regulation of GABA Transmission in the Rat Central Nucleus of the Amygdala. AU - Khom,Sophia, AU - Wolfe,Sarah A, AU - Patel,Reesha R, AU - Kirson,Dean, AU - Hedges,David M, AU - Varodayan,Florence P, AU - Bajo,Michal, AU - Roberto,Marisa, Y1 - 2020/08/07/ PY - 2020/03/30/received PY - 2020/07/08/revised PY - 2020/07/14/accepted PY - 2020/8/10/pubmed PY - 2021/1/2/medline PY - 2020/8/10/entrez KW - GABA KW - alcohol use disorder KW - central amygdala KW - electrophysiology KW - ethanol KW - serotonin SP - 6842 EP - 6853 JF - The Journal of neuroscience : the official journal of the Society for Neuroscience JO - J Neurosci VL - 40 IS - 36 N2 - 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. SN - 1529-2401 UR - https://www.unboundmedicine.com/medline/citation/32769108/Alcohol_Dependence_and_Withdrawal_Impair_Serotonergic_Regulation_of_GABA_Transmission_in_the_Rat_Central_Nucleus_of_the_Amygdala_ L2 - http://www.jneurosci.org/cgi/pmidlookup?view=long&pmid=32769108 DB - PRIME DP - Unbound Medicine ER -