Cessation of fluoxetine treatment increases alcohol seeking during relapse and dysregulates endocannabinoid and glutamatergic signaling in the central amygdala

Juan Suárez; Sophia Khom; Francisco Alén; Luis A. Natividad; Florence P. Varodayan; Reesha R. Patel; Dean Kirson; Rocío Arco; Antonio Ballesta; Michal Bajo; Leticia Rubio; Rémi Martin-Fardon; Fernando Rodríguez de Fonseca; Marisa Roberto

doi:10.1111/adb.12813

Cessation of fluoxetine treatment increases alcohol seeking during relapse and dysregulates endocannabinoid and glutamatergic signaling in the central amygdala

Juan Suárez^*, Sophia Khom, Francisco Alén, Luis A. Natividad, Florence P. Varodayan, Reesha R. Patel, Dean Kirson, Rocío Arco, Antonio Ballesta, Michal Bajo, Leticia Rubio, Rémi Martin-Fardon, Fernando Rodríguez de Fonseca, Marisa Roberto^*

^*Corresponding author for this work

Psychiatry and Behavioral Sciences

Research output: Contribution to journal › Article › peer-review

10 Scopus citations

Abstract

Administration of selective serotonin reuptake inhibitors (SSRIs), typically used as antidepressants, induces long-lasting behavioral changes associated with alcohol use disorder (AUD). However, the contribution of SSRI (fluoxetine)-induced alterations in neurobiological processes underlying alcohol relapse such as endocannabinoid and glutamate signaling in the central amygdala (CeA) remains largely unknown. We utilized an integrative approach to study the effects of repeated fluoxetine administration during abstinence on ethanol drinking. Gene expression and biochemical and electrophysiological studies explored the hypothesis that dysregulation in glutamatergic and endocannabinoid mechanisms in the CeA underlie the susceptibility to alcohol relapse. Cessation of daily treatment with fluoxetine (10 mg/kg) during abstinence resulted in a marked increase in ethanol seeking during re-exposure periods. The increase in ethanol self-administration was associated with (a) reductions in levels of the endocannabinoids N-arachidonoylethanolomine and 2-arachidonoylglycerol in the CeA, (b) increased amygdalar gene expression of cannabinoid type-1 receptor (CB1), N-acyl phosphatidylethanolamine phospholipase D (Nape-pld), fatty acid amid hydrolase (Faah), (c) decreased amygdalar gene expression of ionotropic AMPA (GluA2 and GluA4) and metabotropic (mGlu3) glutamate receptors, and (d) increased glutamatergic receptor function. Overall, our data suggest that the administration of the antidepressant fluoxetine during abstinence dysregulates endocannabinoid signaling and glutamatergic receptor function in the amygdala, facts that likely facilitate alcohol drinking behavior during relapse.

Original language	English (US)
Article number	e12813
Journal	Addiction Biology
Volume	25
Issue number	5
DOIs	https://doi.org/10.1111/adb.12813
State	Published - Sep 1 2020

Funding

This work was supported by the Fulbright Visiting Scholar Program, United States Department of State, Ministerio de Educación, Cultura y Deporte (J.S.: CAS16/00038); RETICS Red de Trastornos Adictivos, Instituto de Salud Carlos III (ISCIII), Ministerio de Economía y Competitividad (MINECO), and European Regional Development Funds–European Union (ERDF-EU) (RD16/0017/0001); Plan Nacional sobre Drogas, Ministerio de Sanidad, Servicios Sociales e Igualdad (J.S.: PND2015/047; F.R.F.: PND2018/044); Instituto de Salud Carlos III, MINECO co-funded by ERDF-EU (J.S.: PI16/01374; F.R.F.: PI16/01698). J.S. holds a “Miguel Servet II” research contract from the National System of Health, ISCIII, ERDF-EU (CPII17/00024). S.K. was supported by the Austrian Science Fund FWF (J-3942-B30). This work was also supported by grants from the National Institutes of Health: K99 AA025393 (L.A.N.), K99 AA025408 (F.P.V.), K99 AA026638 (D.K.), F32 AA026865 (R.R.P.), AA024146 (R.M.F.), AA022249 (R.M.F.), AA015566 (M.R.), AA017447 (M.R.), AA021491 (M.R.), AA013498 (M.R.), and P60 AA006420 (M.R. and R.M.F.).

Keywords

alcohol
amygdala
antidepressant
cannabinoid
glutamate
relapse

ASJC Scopus subject areas

Medicine (miscellaneous)
Pharmacology
Psychiatry and Mental health

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1111/adb.12813

Cite this

Suárez, J., Khom, S., Alén, F., Natividad, L. A., Varodayan, F. P., Patel, R. R., Kirson, D., Arco, R., Ballesta, A., Bajo, M., Rubio, L., Martin-Fardon, R., Rodríguez de Fonseca, F., & Roberto, M. (2020). Cessation of fluoxetine treatment increases alcohol seeking during relapse and dysregulates endocannabinoid and glutamatergic signaling in the central amygdala. Addiction Biology, 25(5), Article e12813. https://doi.org/10.1111/adb.12813

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title = "Cessation of fluoxetine treatment increases alcohol seeking during relapse and dysregulates endocannabinoid and glutamatergic signaling in the central amygdala",

abstract = "Administration of selective serotonin reuptake inhibitors (SSRIs), typically used as antidepressants, induces long-lasting behavioral changes associated with alcohol use disorder (AUD). However, the contribution of SSRI (fluoxetine)-induced alterations in neurobiological processes underlying alcohol relapse such as endocannabinoid and glutamate signaling in the central amygdala (CeA) remains largely unknown. We utilized an integrative approach to study the effects of repeated fluoxetine administration during abstinence on ethanol drinking. Gene expression and biochemical and electrophysiological studies explored the hypothesis that dysregulation in glutamatergic and endocannabinoid mechanisms in the CeA underlie the susceptibility to alcohol relapse. Cessation of daily treatment with fluoxetine (10 mg/kg) during abstinence resulted in a marked increase in ethanol seeking during re-exposure periods. The increase in ethanol self-administration was associated with (a) reductions in levels of the endocannabinoids N-arachidonoylethanolomine and 2-arachidonoylglycerol in the CeA, (b) increased amygdalar gene expression of cannabinoid type-1 receptor (CB1), N-acyl phosphatidylethanolamine phospholipase D (Nape-pld), fatty acid amid hydrolase (Faah), (c) decreased amygdalar gene expression of ionotropic AMPA (GluA2 and GluA4) and metabotropic (mGlu3) glutamate receptors, and (d) increased glutamatergic receptor function. Overall, our data suggest that the administration of the antidepressant fluoxetine during abstinence dysregulates endocannabinoid signaling and glutamatergic receptor function in the amygdala, facts that likely facilitate alcohol drinking behavior during relapse.",

keywords = "alcohol, amygdala, antidepressant, cannabinoid, glutamate, relapse",

author = "Juan Su{\'a}rez and Sophia Khom and Francisco Al{\'e}n and Natividad, {Luis A.} and Varodayan, {Florence P.} and Patel, {Reesha R.} and Dean Kirson and Roc{\'i}o Arco and Antonio Ballesta and Michal Bajo and Leticia Rubio and R{\'e}mi Martin-Fardon and {Rodr{\'i}guez de Fonseca}, Fernando and Marisa Roberto",

note = "Funding Information: This work was supported by the Fulbright Visiting Scholar Program, United States Department of State, Ministerio de Educaci{\'o}n, Cultura y Deporte (J.S.: CAS16/00038); RETICS Red de Trastornos Adictivos, Instituto de Salud Carlos III (ISCIII), Ministerio de Econom{\'i}a y Competitividad (MINECO), and European Regional Development Funds–European Union (ERDF-EU) (RD16/0017/0001); Plan Nacional sobre Drogas, Ministerio de Sanidad, Servicios Sociales e Igualdad (J.S.: PND2015/047; F.R.F.: PND2018/044); Instituto de Salud Carlos III, MINECO co-funded by ERDF-EU (J.S.: PI16/01374; F.R.F.: PI16/01698). J.S. holds a “Miguel Servet II” research contract from the National System of Health, ISCIII, ERDF-EU (CPII17/00024). S.K. was supported by the Austrian Science Fund FWF (J-3942-B30). This work was also supported by grants from the National Institutes of Health: K99 AA025393 (L.A.N.), K99 AA025408 (F.P.V.), K99 AA026638 (D.K.), F32 AA026865 (R.R.P.), AA024146 (R.M.F.), AA022249 (R.M.F.), AA015566 (M.R.), AA017447 (M.R.), AA021491 (M.R.), AA013498 (M.R.), and P60 AA006420 (M.R. and R.M.F.). Publisher Copyright: {\textcopyright} 2019 Society for the Study of Addiction",

year = "2020",

month = sep,

day = "1",

doi = "10.1111/adb.12813",

language = "English (US)",

volume = "25",

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Suárez, J, Khom, S, Alén, F, Natividad, LA, Varodayan, FP, Patel, RR, Kirson, D, Arco, R, Ballesta, A, Bajo, M, Rubio, L, Martin-Fardon, R, Rodríguez de Fonseca, F & Roberto, M 2020, 'Cessation of fluoxetine treatment increases alcohol seeking during relapse and dysregulates endocannabinoid and glutamatergic signaling in the central amygdala', Addiction Biology, vol. 25, no. 5, e12813. https://doi.org/10.1111/adb.12813

TY - JOUR

T1 - Cessation of fluoxetine treatment increases alcohol seeking during relapse and dysregulates endocannabinoid and glutamatergic signaling in the central amygdala

AU - Suárez, Juan

AU - Khom, Sophia

AU - Alén, Francisco

AU - Natividad, Luis A.

AU - Varodayan, Florence P.

AU - Patel, Reesha R.

AU - Kirson, Dean

AU - Arco, Rocío

AU - Ballesta, Antonio

AU - Bajo, Michal

AU - Rubio, Leticia

AU - Martin-Fardon, Rémi

AU - Rodríguez de Fonseca, Fernando

AU - Roberto, Marisa

N1 - Funding Information: This work was supported by the Fulbright Visiting Scholar Program, United States Department of State, Ministerio de Educación, Cultura y Deporte (J.S.: CAS16/00038); RETICS Red de Trastornos Adictivos, Instituto de Salud Carlos III (ISCIII), Ministerio de Economía y Competitividad (MINECO), and European Regional Development Funds–European Union (ERDF-EU) (RD16/0017/0001); Plan Nacional sobre Drogas, Ministerio de Sanidad, Servicios Sociales e Igualdad (J.S.: PND2015/047; F.R.F.: PND2018/044); Instituto de Salud Carlos III, MINECO co-funded by ERDF-EU (J.S.: PI16/01374; F.R.F.: PI16/01698). J.S. holds a “Miguel Servet II” research contract from the National System of Health, ISCIII, ERDF-EU (CPII17/00024). S.K. was supported by the Austrian Science Fund FWF (J-3942-B30). This work was also supported by grants from the National Institutes of Health: K99 AA025393 (L.A.N.), K99 AA025408 (F.P.V.), K99 AA026638 (D.K.), F32 AA026865 (R.R.P.), AA024146 (R.M.F.), AA022249 (R.M.F.), AA015566 (M.R.), AA017447 (M.R.), AA021491 (M.R.), AA013498 (M.R.), and P60 AA006420 (M.R. and R.M.F.). Publisher Copyright: © 2019 Society for the Study of Addiction

PY - 2020/9/1

Y1 - 2020/9/1

N2 - Administration of selective serotonin reuptake inhibitors (SSRIs), typically used as antidepressants, induces long-lasting behavioral changes associated with alcohol use disorder (AUD). However, the contribution of SSRI (fluoxetine)-induced alterations in neurobiological processes underlying alcohol relapse such as endocannabinoid and glutamate signaling in the central amygdala (CeA) remains largely unknown. We utilized an integrative approach to study the effects of repeated fluoxetine administration during abstinence on ethanol drinking. Gene expression and biochemical and electrophysiological studies explored the hypothesis that dysregulation in glutamatergic and endocannabinoid mechanisms in the CeA underlie the susceptibility to alcohol relapse. Cessation of daily treatment with fluoxetine (10 mg/kg) during abstinence resulted in a marked increase in ethanol seeking during re-exposure periods. The increase in ethanol self-administration was associated with (a) reductions in levels of the endocannabinoids N-arachidonoylethanolomine and 2-arachidonoylglycerol in the CeA, (b) increased amygdalar gene expression of cannabinoid type-1 receptor (CB1), N-acyl phosphatidylethanolamine phospholipase D (Nape-pld), fatty acid amid hydrolase (Faah), (c) decreased amygdalar gene expression of ionotropic AMPA (GluA2 and GluA4) and metabotropic (mGlu3) glutamate receptors, and (d) increased glutamatergic receptor function. Overall, our data suggest that the administration of the antidepressant fluoxetine during abstinence dysregulates endocannabinoid signaling and glutamatergic receptor function in the amygdala, facts that likely facilitate alcohol drinking behavior during relapse.

AB - Administration of selective serotonin reuptake inhibitors (SSRIs), typically used as antidepressants, induces long-lasting behavioral changes associated with alcohol use disorder (AUD). However, the contribution of SSRI (fluoxetine)-induced alterations in neurobiological processes underlying alcohol relapse such as endocannabinoid and glutamate signaling in the central amygdala (CeA) remains largely unknown. We utilized an integrative approach to study the effects of repeated fluoxetine administration during abstinence on ethanol drinking. Gene expression and biochemical and electrophysiological studies explored the hypothesis that dysregulation in glutamatergic and endocannabinoid mechanisms in the CeA underlie the susceptibility to alcohol relapse. Cessation of daily treatment with fluoxetine (10 mg/kg) during abstinence resulted in a marked increase in ethanol seeking during re-exposure periods. The increase in ethanol self-administration was associated with (a) reductions in levels of the endocannabinoids N-arachidonoylethanolomine and 2-arachidonoylglycerol in the CeA, (b) increased amygdalar gene expression of cannabinoid type-1 receptor (CB1), N-acyl phosphatidylethanolamine phospholipase D (Nape-pld), fatty acid amid hydrolase (Faah), (c) decreased amygdalar gene expression of ionotropic AMPA (GluA2 and GluA4) and metabotropic (mGlu3) glutamate receptors, and (d) increased glutamatergic receptor function. Overall, our data suggest that the administration of the antidepressant fluoxetine during abstinence dysregulates endocannabinoid signaling and glutamatergic receptor function in the amygdala, facts that likely facilitate alcohol drinking behavior during relapse.

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KW - amygdala

KW - antidepressant

KW - cannabinoid

KW - glutamate

KW - relapse

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JO - Addiction Biology

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ER -

Cessation of fluoxetine treatment increases alcohol seeking during relapse and dysregulates endocannabinoid and glutamatergic signaling in the central amygdala

Abstract

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ASJC Scopus subject areas

UN SDGs

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