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Persistent increase of accumbens cocaine ensemble excitability induced by IRK downregulation after withdrawal mediates the incubation of cocaine craving
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...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9812793/ https://www.ncbi.nlm.nih.gov/pubmed/36481931 http://dx.doi.org/10.1038/s41380-022-01884-1 |
Sumario: | 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 Kir(2.1) currents after 30-day withdrawal. Overexpression of Kir(2.1) in NAcSh cocaine-ensembles restored neuronal membrane excitability and suppressed cue-induced drug-seeking after 30-day withdrawal. Expression of dominant-negative Kir(2.1) in NAcSh cocaine-ensembles enhanced neuronal membrane excitability and accelerated incubation of cocaine craving. Our results provide a cellular mechanism that the downregulation of Kir(2.1) functions in NAcSh cocaine-ensembles induced by prolonged withdrawal mediates the enhancement of ensemble membrane excitability, leading to incubation of cocaine craving. |
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