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Tropisetron Facilitates Footshock Suppression of Compulsive Cocaine Seeking
BACKGROUND: The hallmark characteristics of the murine model of drug addiction include the escalation of cocaine consumption and compulsive punishment-resistant drug seeking. In this study, we evaluated the motivation for drug seeking in cocaine self-administering rats exposed to an escalated dosing...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6754734/ https://www.ncbi.nlm.nih.gov/pubmed/31125405 http://dx.doi.org/10.1093/ijnp/pyz023 |
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author | Zhou, Yue-Qing Zhang, Lan-Yuan Yu, Zhi-Peng Zhang, Xiao-Qin Shi, Jie Shen, Hao-Wei |
author_facet | Zhou, Yue-Qing Zhang, Lan-Yuan Yu, Zhi-Peng Zhang, Xiao-Qin Shi, Jie Shen, Hao-Wei |
author_sort | Zhou, Yue-Qing |
collection | PubMed |
description | BACKGROUND: The hallmark characteristics of the murine model of drug addiction include the escalation of cocaine consumption and compulsive punishment-resistant drug seeking. In this study, we evaluated the motivation for drug seeking in cocaine self-administering rats exposed to an escalated dosing regimen that endeavored to mimic the characteristic of escalating drug intake in human addicts. Tropisetron is a 5-HT(3) receptor antagonist and α7-nicotinic receptor partial agonist. Utilizing rats trained on the escalated-dosing regimen, we examined the effects of tropisetron on control over compulsive drug-seeking behavior that was defined as footshock-resistant lever pressing. METHODS: Rats were trained to self-administer cocaine with incremental-infusion doses (from 0.6 to 2.4 mg/kg/infusion) across training sessions (3 h/session) or with a long-access paradigm (i.e., 0.6 mg/kg/infusion, 6 h/d training session). The drug-seeking motivations of 2 groups were estimated by the patterns of drug intake and progressive-ratio schedule. The compulsivity for drug seeking of the group with an escalated dose was further evaluated using the footshock-associated seeking-taking chain task. RESULTS: The rats trained on the dose-escalated protocol achieved the same levels of motivated drug seeking as those subjected to a long-access paradigm, as indicated by cocaine intake per training session and breakpoints on a progressive ratio schedule. Tropisetron attenuated compulsive behavior of rats when pressing of the seeking lever potentially led to footshock. Intriguingly, tropisetron did not change the motivation to seek cocaine when footshock was absent. Tropisetron had no effect on locomotor activities or saccharin self-administration. CONCLUSIONS: These results demonstrate that tropisetron restored control over compulsive cocaine seeking, and they indicate that 5-HT(3)/α7-nicotinic receptors may be potential therapeutic targets for relieving compulsive drug seeking. |
format | Online Article Text |
id | pubmed-6754734 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-67547342019-09-25 Tropisetron Facilitates Footshock Suppression of Compulsive Cocaine Seeking Zhou, Yue-Qing Zhang, Lan-Yuan Yu, Zhi-Peng Zhang, Xiao-Qin Shi, Jie Shen, Hao-Wei Int J Neuropsychopharmacol Regular Research Articles BACKGROUND: The hallmark characteristics of the murine model of drug addiction include the escalation of cocaine consumption and compulsive punishment-resistant drug seeking. In this study, we evaluated the motivation for drug seeking in cocaine self-administering rats exposed to an escalated dosing regimen that endeavored to mimic the characteristic of escalating drug intake in human addicts. Tropisetron is a 5-HT(3) receptor antagonist and α7-nicotinic receptor partial agonist. Utilizing rats trained on the escalated-dosing regimen, we examined the effects of tropisetron on control over compulsive drug-seeking behavior that was defined as footshock-resistant lever pressing. METHODS: Rats were trained to self-administer cocaine with incremental-infusion doses (from 0.6 to 2.4 mg/kg/infusion) across training sessions (3 h/session) or with a long-access paradigm (i.e., 0.6 mg/kg/infusion, 6 h/d training session). The drug-seeking motivations of 2 groups were estimated by the patterns of drug intake and progressive-ratio schedule. The compulsivity for drug seeking of the group with an escalated dose was further evaluated using the footshock-associated seeking-taking chain task. RESULTS: The rats trained on the dose-escalated protocol achieved the same levels of motivated drug seeking as those subjected to a long-access paradigm, as indicated by cocaine intake per training session and breakpoints on a progressive ratio schedule. Tropisetron attenuated compulsive behavior of rats when pressing of the seeking lever potentially led to footshock. Intriguingly, tropisetron did not change the motivation to seek cocaine when footshock was absent. Tropisetron had no effect on locomotor activities or saccharin self-administration. CONCLUSIONS: These results demonstrate that tropisetron restored control over compulsive cocaine seeking, and they indicate that 5-HT(3)/α7-nicotinic receptors may be potential therapeutic targets for relieving compulsive drug seeking. Oxford University Press 2019-05-24 /pmc/articles/PMC6754734/ /pubmed/31125405 http://dx.doi.org/10.1093/ijnp/pyz023 Text en © The Author(s) 2019. Published by Oxford University Press on behalf of CINP. http://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com |
spellingShingle | Regular Research Articles Zhou, Yue-Qing Zhang, Lan-Yuan Yu, Zhi-Peng Zhang, Xiao-Qin Shi, Jie Shen, Hao-Wei Tropisetron Facilitates Footshock Suppression of Compulsive Cocaine Seeking |
title | Tropisetron Facilitates Footshock Suppression of Compulsive Cocaine Seeking |
title_full | Tropisetron Facilitates Footshock Suppression of Compulsive Cocaine Seeking |
title_fullStr | Tropisetron Facilitates Footshock Suppression of Compulsive Cocaine Seeking |
title_full_unstemmed | Tropisetron Facilitates Footshock Suppression of Compulsive Cocaine Seeking |
title_short | Tropisetron Facilitates Footshock Suppression of Compulsive Cocaine Seeking |
title_sort | tropisetron facilitates footshock suppression of compulsive cocaine seeking |
topic | Regular Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6754734/ https://www.ncbi.nlm.nih.gov/pubmed/31125405 http://dx.doi.org/10.1093/ijnp/pyz023 |
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