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
N1 - Funding Information:
This work was supported by National Institutes of Health/National Institute on Alcohol Abuse and Alcoholism Grants AA006420, AA013498, AA015566, AA017477, AA027700, AA007456, and AA021491, all to M.R., Grant AA026865 to R.R.P., Grants AA025262 and AA026638 to D.K., and Grant AA025408 to F.P.V.; and Pearson Center for Alcoholism and Addiction Research and the Austrian Science Fund FWF Erwin Schrödinger Fellowship J-3942-B30 to S.K. This is Scripps manuscript number 29963. Correspondence should be addressed to Marisa Roberto at mroberto@scripps.edu. https://doi.org/10.1523/JNEUROSCI.0733-20.2020 Copyright © 2020 the authors
Publisher Copyright:
Copyright © 2020 the authors
PY - 2020/9/2
Y1 - 2020/9/2
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 Accordingly, 5-HT abolished spontaneous neuronal firing in naive and dependent rats but had bidirectional effects in withdrawn.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.
AB - 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.
KW - Alcohol use disorder
KW - Central amygdala
KW - Electrophysiology
KW - Ethanol
KW - GABA
KW - Serotonin
UR - http://www.scopus.com/inward/record.url?scp=85090275344&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85090275344&partnerID=8YFLogxK
U2 - 10.1523/JNEUROSCI.0733-20.2020
DO - 10.1523/JNEUROSCI.0733-20.2020
M3 - Article
C2 - 32769108
AN - SCOPUS:85090275344
SN - 0270-6474
VL - 40
SP - 6842
EP - 6853
JO - Journal of Neuroscience
JF - Journal of Neuroscience
IS - 36
ER -
