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Disrupting Reconsolidation by Systemic Inhibition of mTOR Kinase via Rapamycin Reduces Cocaine-Seeking Behavior

Drug addiction is considered maladaptive learning, and drug-related memories aroused by the presence of drug related stimuli (drug context or drug-associated cues) promote recurring craving and reinstatement of drug seeking. The mammalian target of rapamycin signaling pathway is involved in reconsol...

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Autores principales: Zhang, Fushen, Huang, Shihao, Bu, Haiyan, Zhou, Yu, Chen, Lixiang, Kang, Ziliu, Chen, Liangpei, Yan, He, Yang, Chang, Yan, Jie, Jian, Xiaohong, Luo, Yixiao
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8064688/
https://www.ncbi.nlm.nih.gov/pubmed/33897438
http://dx.doi.org/10.3389/fphar.2021.652865
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author Zhang, Fushen
Huang, Shihao
Bu, Haiyan
Zhou, Yu
Chen, Lixiang
Kang, Ziliu
Chen, Liangpei
Yan, He
Yang, Chang
Yan, Jie
Jian, Xiaohong
Luo, Yixiao
author_facet Zhang, Fushen
Huang, Shihao
Bu, Haiyan
Zhou, Yu
Chen, Lixiang
Kang, Ziliu
Chen, Liangpei
Yan, He
Yang, Chang
Yan, Jie
Jian, Xiaohong
Luo, Yixiao
author_sort Zhang, Fushen
collection PubMed
description Drug addiction is considered maladaptive learning, and drug-related memories aroused by the presence of drug related stimuli (drug context or drug-associated cues) promote recurring craving and reinstatement of drug seeking. The mammalian target of rapamycin signaling pathway is involved in reconsolidation of drug memories in conditioned place preference and alcohol self-administration (SA) paradigms. Here, we explored the effect of mTOR inhibition on reconsolidation of addiction memory using cocaine self-administration paradigm. Rats received intravenous cocaine self-administration training for 10 consecutive days, during which a light/tone conditioned stimulus was paired with each cocaine infusion. After acquisition of the stable cocaine self-administration behaviors, rats were subjected to nosepoke extinction (11 days) to extinguish their behaviors, and then received a 15 min retrieval trial with or without the cocaine-paired tone/light cue delivery or without. Immediately or 6 h after the retrieval trial, rapamycin (10 mg/kg) was administered intraperitoneally. Finally, cue-induced reinstatement, cocaine-priming-induced reinstatement and spontaneous recovery of cocaine-seeking behaviors were assessed in rapamycin previously treated animals, respectively. We found that rapamycin treatment immediately after a retrieval trial decreased subsequent reinstatement of cocaine seeking induced by cues or cocaine itself, and these effects lasted at least for 28 days. In contrast, delayed intraperitoneal injection of rapamycin 6 h after retrieval or rapamycin injection without retrieval had no effects on cocaine-seeking behaviors. These findings indicated that mTOR inhibition within the reconsolidation time-window impairs the reconsolidation of cocaine associated memory, reduces cocaine-seeking behavior and prevents relapse, and these effects are retrieval-dependent and temporal-specific.
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spelling pubmed-80646882021-04-24 Disrupting Reconsolidation by Systemic Inhibition of mTOR Kinase via Rapamycin Reduces Cocaine-Seeking Behavior Zhang, Fushen Huang, Shihao Bu, Haiyan Zhou, Yu Chen, Lixiang Kang, Ziliu Chen, Liangpei Yan, He Yang, Chang Yan, Jie Jian, Xiaohong Luo, Yixiao Front Pharmacol Pharmacology Drug addiction is considered maladaptive learning, and drug-related memories aroused by the presence of drug related stimuli (drug context or drug-associated cues) promote recurring craving and reinstatement of drug seeking. The mammalian target of rapamycin signaling pathway is involved in reconsolidation of drug memories in conditioned place preference and alcohol self-administration (SA) paradigms. Here, we explored the effect of mTOR inhibition on reconsolidation of addiction memory using cocaine self-administration paradigm. Rats received intravenous cocaine self-administration training for 10 consecutive days, during which a light/tone conditioned stimulus was paired with each cocaine infusion. After acquisition of the stable cocaine self-administration behaviors, rats were subjected to nosepoke extinction (11 days) to extinguish their behaviors, and then received a 15 min retrieval trial with or without the cocaine-paired tone/light cue delivery or without. Immediately or 6 h after the retrieval trial, rapamycin (10 mg/kg) was administered intraperitoneally. Finally, cue-induced reinstatement, cocaine-priming-induced reinstatement and spontaneous recovery of cocaine-seeking behaviors were assessed in rapamycin previously treated animals, respectively. We found that rapamycin treatment immediately after a retrieval trial decreased subsequent reinstatement of cocaine seeking induced by cues or cocaine itself, and these effects lasted at least for 28 days. In contrast, delayed intraperitoneal injection of rapamycin 6 h after retrieval or rapamycin injection without retrieval had no effects on cocaine-seeking behaviors. These findings indicated that mTOR inhibition within the reconsolidation time-window impairs the reconsolidation of cocaine associated memory, reduces cocaine-seeking behavior and prevents relapse, and these effects are retrieval-dependent and temporal-specific. Frontiers Media S.A. 2021-04-09 /pmc/articles/PMC8064688/ /pubmed/33897438 http://dx.doi.org/10.3389/fphar.2021.652865 Text en Copyright © 2021 Zhang, Huang, Bu, Zhou, Chen, Kang, Chen, Yan, Yang, Yan, Jian and Luo. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Pharmacology
Zhang, Fushen
Huang, Shihao
Bu, Haiyan
Zhou, Yu
Chen, Lixiang
Kang, Ziliu
Chen, Liangpei
Yan, He
Yang, Chang
Yan, Jie
Jian, Xiaohong
Luo, Yixiao
Disrupting Reconsolidation by Systemic Inhibition of mTOR Kinase via Rapamycin Reduces Cocaine-Seeking Behavior
title Disrupting Reconsolidation by Systemic Inhibition of mTOR Kinase via Rapamycin Reduces Cocaine-Seeking Behavior
title_full Disrupting Reconsolidation by Systemic Inhibition of mTOR Kinase via Rapamycin Reduces Cocaine-Seeking Behavior
title_fullStr Disrupting Reconsolidation by Systemic Inhibition of mTOR Kinase via Rapamycin Reduces Cocaine-Seeking Behavior
title_full_unstemmed Disrupting Reconsolidation by Systemic Inhibition of mTOR Kinase via Rapamycin Reduces Cocaine-Seeking Behavior
title_short Disrupting Reconsolidation by Systemic Inhibition of mTOR Kinase via Rapamycin Reduces Cocaine-Seeking Behavior
title_sort disrupting reconsolidation by systemic inhibition of mtor kinase via rapamycin reduces cocaine-seeking behavior
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8064688/
https://www.ncbi.nlm.nih.gov/pubmed/33897438
http://dx.doi.org/10.3389/fphar.2021.652865
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