Persistent increase of accumbens cocaine ensemble excitability induced by IRK downregulation after withdrawal mediates the incubation of cocaine craving
© 2022. The Author(s)..
The incubation phenomenon, cue-induced drug craving progressively increasing over prolonged withdrawal, accounts for persistent relapse, leading to a dilemma in the treatment of cocaine addiction. The role of neuronal ensembles activated by initial cocaine experience in the incubation phenomenon was unclear. In this study, with cocaine self-administration (SA) models, we found that neuronal ensembles in the nucleus accumbens shell (NAcSh) showed increasing activation induced by cue-induced drug-seeking after 30-day withdrawal. Inhibition or activation of NAcSh cocaine-ensembles suppressed or promoted craving for cocaine, demonstrating a critical role of NAcSh cocaine-ensembles in incubation for cocaine craving. NAcSh cocaine-ensembles showed a specific increase of membrane excitability and a decrease of inward rectifying channels Kir2.1 currents after 30-day withdrawal. Overexpression of Kir2.1 in NAcSh cocaine-ensembles restored neuronal membrane excitability and suppressed cue-induced drug-seeking after 30-day withdrawal. Expression of dominant-negative Kir2.1 in NAcSh cocaine-ensembles enhanced neuronal membrane excitability and accelerated incubation of cocaine craving. Our results provide a cellular mechanism that the downregulation of Kir2.1 functions in NAcSh cocaine-ensembles induced by prolonged withdrawal mediates the enhancement of ensemble membrane excitability, leading to incubation of cocaine craving.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:28 |
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| Enthalten in: |
Molecular psychiatry - 28(2023), 1 vom: 08. Jan., Seite 448-462 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
He, Guanhong [VerfasserIn] |
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| Links: |
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| Themen: |
Cocaine |
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| Anmerkungen: |
Date Completed 09.01.2023 Date Revised 12.05.2023 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1038/s41380-022-01884-1 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM349942617 |
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| 520 | |a © 2022. The Author(s). | ||
| 520 | |a The incubation phenomenon, cue-induced drug craving progressively increasing over prolonged withdrawal, accounts for persistent relapse, leading to a dilemma in the treatment of cocaine addiction. The role of neuronal ensembles activated by initial cocaine experience in the incubation phenomenon was unclear. In this study, with cocaine self-administration (SA) models, we found that neuronal ensembles in the nucleus accumbens shell (NAcSh) showed increasing activation induced by cue-induced drug-seeking after 30-day withdrawal. Inhibition or activation of NAcSh cocaine-ensembles suppressed or promoted craving for cocaine, demonstrating a critical role of NAcSh cocaine-ensembles in incubation for cocaine craving. NAcSh cocaine-ensembles showed a specific increase of membrane excitability and a decrease of inward rectifying channels Kir2.1 currents after 30-day withdrawal. Overexpression of Kir2.1 in NAcSh cocaine-ensembles restored neuronal membrane excitability and suppressed cue-induced drug-seeking after 30-day withdrawal. Expression of dominant-negative Kir2.1 in NAcSh cocaine-ensembles enhanced neuronal membrane excitability and accelerated incubation of cocaine craving. Our results provide a cellular mechanism that the downregulation of Kir2.1 functions in NAcSh cocaine-ensembles induced by prolonged withdrawal mediates the enhancement of ensemble membrane excitability, leading to incubation of cocaine craving | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 7 | |a Cocaine |2 NLM | |
| 650 | 7 | |a I5Y540LHVR |2 NLM | |
| 700 | 1 | |a Huai, Ziqing |e verfasserin |4 aut | |
| 700 | 1 | |a Jiang, Changyou |e verfasserin |4 aut | |
| 700 | 1 | |a Huang, Bing |e verfasserin |4 aut | |
| 700 | 1 | |a Tian, Zhen |e verfasserin |4 aut | |
| 700 | 1 | |a Le, Qiumin |e verfasserin |4 aut | |
| 700 | 1 | |a Fan, Guangyuan |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Haibo |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Feifei |e verfasserin |4 aut | |
| 700 | 1 | |a Ma, Lan |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Xing |e verfasserin |4 aut | |
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