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Chronic fluoxetine treatment impairs motivation and reward learning by affecting neuronal plasticity in the central amygdala


Puścian, Alicja; Winiarski, Maciej; Łęski, Szymon; Charzewski, Łukasz; Nikolaev, Tomasz; Borowska, Joanna; Dzik, Jakub M; Bijata, Monika; Lipp, Hans-Peter; Dziembowska, Magdalena; Knapska, Ewelina (2021). Chronic fluoxetine treatment impairs motivation and reward learning by affecting neuronal plasticity in the central amygdala. British Journal of Pharmacology, 178(3):672-688.

Abstract

Background and Purpose The therapeutic effects of fluoxetine (FLX) are believed to be due to its potency for increasing neuronal plasticity and reversing some learning deficits. Nevertheless, a growing amount of evidence shows the adverse effects of the drug on cognition and some forms of neuronal plasticity.

EXPERIMENTAL APPROACH

To study the effects of chronic FLX treatment we combine an automated assessment of motivation and learning in mice with an investigation of various forms of neuronal plasticity in the central (CeA) and basolateral amygdala (BLA). We use immunohistochemistry to visualize neuronal types and perineuronal nets (PNN), and DI-staining to assess dendritic spine morphology. Gel zymography is used to test FLX's impact on matrix metalloproteinase-9 (MMP-9), an enzyme involved in synaptic plasticity.

KEY RESULTS

We show that chronic FLX treatment in non-stressed mice increases PNN-dependent plasticity in the BLA, while simultaneously impairing MMP-9-dependent plasticity in the CeA. Further, we illustrate how the latter contributes to anhedonia and deficits of reward learning. Behavioral impairments are accompanied by alterations in morphology of dendritic spines in the CeA towards a more immature state, most likely reflecting animals' inability to adapt. We strengthen the link between the adverse effects of FLX and its influence on MMP-9 by showing that behavior of MMP-9 knock-out animals remains unaffected by the drug.

CONCLUSION AND IMPLICATIONS

In conclusion, chronic FLX treatment differentially affects various forms of neuronal plasticity, which may explain its contradicting effects on the brain and behavior. Presented findings are of immediate clinical relevance since reported side effects of FLX pose a potential threat to patients.

Abstract

Background and Purpose The therapeutic effects of fluoxetine (FLX) are believed to be due to its potency for increasing neuronal plasticity and reversing some learning deficits. Nevertheless, a growing amount of evidence shows the adverse effects of the drug on cognition and some forms of neuronal plasticity.

EXPERIMENTAL APPROACH

To study the effects of chronic FLX treatment we combine an automated assessment of motivation and learning in mice with an investigation of various forms of neuronal plasticity in the central (CeA) and basolateral amygdala (BLA). We use immunohistochemistry to visualize neuronal types and perineuronal nets (PNN), and DI-staining to assess dendritic spine morphology. Gel zymography is used to test FLX's impact on matrix metalloproteinase-9 (MMP-9), an enzyme involved in synaptic plasticity.

KEY RESULTS

We show that chronic FLX treatment in non-stressed mice increases PNN-dependent plasticity in the BLA, while simultaneously impairing MMP-9-dependent plasticity in the CeA. Further, we illustrate how the latter contributes to anhedonia and deficits of reward learning. Behavioral impairments are accompanied by alterations in morphology of dendritic spines in the CeA towards a more immature state, most likely reflecting animals' inability to adapt. We strengthen the link between the adverse effects of FLX and its influence on MMP-9 by showing that behavior of MMP-9 knock-out animals remains unaffected by the drug.

CONCLUSION AND IMPLICATIONS

In conclusion, chronic FLX treatment differentially affects various forms of neuronal plasticity, which may explain its contradicting effects on the brain and behavior. Presented findings are of immediate clinical relevance since reported side effects of FLX pose a potential threat to patients.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Anatomy
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Date:February 2021
Deposited On:07 Dec 2020 15:40
Last Modified:14 Jan 2021 02:09
Publisher:Wiley-Blackwell Publishing, Inc.
ISSN:0007-1188
OA Status:Closed
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1111/bph.15319
PubMed ID:33171527

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