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Escalation of intravenous fentanyl self-administration and assessment of withdrawal behavior in male and female mice.

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Title: Escalation of intravenous fentanyl self-administration and assessment of withdrawal behavior in male and female mice.
Authors: Chen, Yueyi (AUTHOR), Xiao, Tiange (AUTHOR), Kimbrough, Adam (AUTHOR)
Source: Psychopharmacology. Jun2025, Vol. 242 Issue 6, p1419-1435. 17p.
Subjects: Fentanyl, Drug-seeking behavior, Drug administration, Pain threshold, Laboratory mice, Anxiety, Opioid abuse, Withdrawal (Psychology)
Abstract: Rationale: The rise in overdose deaths from synthetic opioids, especially fentanyl, necessitates the development of preclinical models to study fentanyl use disorder (FUD). While there has been progress with rodent models, additional translationally relevant models are needed to examine excessive fentanyl intake and withdrawal signs. Objective: The current study aimed to develop a translationally relevant preclinical mouse model of FUD by employing chronic intravenous fentanyl self-administration (IVSA). Methods: The study performed intravenous self-administration (IVSA) of fentanyl in male and female C57BL/6J mice for 14 days. Mechanical pain sensitivity during withdrawal was assessed using the von Frey test. Anxiety-like behavior was evaluated via the open field test one week into abstinence, and drug seeking behavior after extended abstinence was assessed at four weeks abstinence. Results: Both male and female mice demonstrated a significant escalation in fentanyl intake over the 14 days of self-administration, with significant front-loading observed in the final days of self-administration. Mice showed increased mechanical pain sensitivity at 36 and 48hours withdrawal from fentanyl. At 1-week abstinence from fentanyl, mice exhibited increased anxiety-like behavior compared to naive mice. Four weeks into abstinence from fentanyl, mice maintained lever-pressing behavior on the previous reward-associated active lever, with significantly higher active lever pressing compared to inactive lever pressing. Conclusions: The study establishes a translationally relevant mouse model of IVSA of fentanyl, effectively encapsulating critical aspects of FUD, including escalation of drug intake, front-loading behavior, withdrawal signs, and drug-seeking behavior into extended abstinence. This model offers a robust basis for further exploration into behavioral and neurobiological mechanisms involved in fentanyl dependence and potential therapeutic strategies. [ABSTRACT FROM AUTHOR]
Copyright of Psychopharmacology is the property of Springer Nature and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
Database: Psychology and Behavioral Sciences Collection
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  Data: Escalation of intravenous fentanyl self-administration and assessment of withdrawal behavior in male and female mice.
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  Data: <searchLink fieldCode="AR" term="%22Chen%2C+Yueyi%22">Chen, Yueyi</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Xiao%2C+Tiange%22">Xiao, Tiange</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Kimbrough%2C+Adam%22">Kimbrough, Adam</searchLink> (AUTHOR)
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  Data: <searchLink fieldCode="JN" term="%22Psychopharmacology%22">Psychopharmacology</searchLink>. Jun2025, Vol. 242 Issue 6, p1419-1435. 17p.
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  Data: <searchLink fieldCode="DE" term="%22Fentanyl%22">Fentanyl</searchLink><br /><searchLink fieldCode="DE" term="%22Drug-seeking+behavior%22">Drug-seeking behavior</searchLink><br /><searchLink fieldCode="DE" term="%22Drug+administration%22">Drug administration</searchLink><br /><searchLink fieldCode="DE" term="%22Pain+threshold%22">Pain threshold</searchLink><br /><searchLink fieldCode="DE" term="%22Laboratory+mice%22">Laboratory mice</searchLink><br /><searchLink fieldCode="DE" term="%22Anxiety%22">Anxiety</searchLink><br /><searchLink fieldCode="DE" term="%22Opioid+abuse%22">Opioid abuse</searchLink><br /><searchLink fieldCode="DE" term="%22Withdrawal+%28Psychology%29%22">Withdrawal (Psychology)</searchLink>
– Name: Abstract
  Label: Abstract
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  Data: Rationale: The rise in overdose deaths from synthetic opioids, especially fentanyl, necessitates the development of preclinical models to study fentanyl use disorder (FUD). While there has been progress with rodent models, additional translationally relevant models are needed to examine excessive fentanyl intake and withdrawal signs. Objective: The current study aimed to develop a translationally relevant preclinical mouse model of FUD by employing chronic intravenous fentanyl self-administration (IVSA). Methods: The study performed intravenous self-administration (IVSA) of fentanyl in male and female C57BL/6J mice for 14 days. Mechanical pain sensitivity during withdrawal was assessed using the von Frey test. Anxiety-like behavior was evaluated via the open field test one week into abstinence, and drug seeking behavior after extended abstinence was assessed at four weeks abstinence. Results: Both male and female mice demonstrated a significant escalation in fentanyl intake over the 14 days of self-administration, with significant front-loading observed in the final days of self-administration. Mice showed increased mechanical pain sensitivity at 36 and 48hours withdrawal from fentanyl. At 1-week abstinence from fentanyl, mice exhibited increased anxiety-like behavior compared to naive mice. Four weeks into abstinence from fentanyl, mice maintained lever-pressing behavior on the previous reward-associated active lever, with significantly higher active lever pressing compared to inactive lever pressing. Conclusions: The study establishes a translationally relevant mouse model of IVSA of fentanyl, effectively encapsulating critical aspects of FUD, including escalation of drug intake, front-loading behavior, withdrawal signs, and drug-seeking behavior into extended abstinence. This model offers a robust basis for further exploration into behavioral and neurobiological mechanisms involved in fentanyl dependence and potential therapeutic strategies. [ABSTRACT FROM AUTHOR]
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  Data: <i>Copyright of Psychopharmacology is the property of Springer Nature and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
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        Value: 10.1007/s00213-024-06739-x
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        Text: English
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        Type: general
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      – SubjectFull: Drug administration
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      – SubjectFull: Laboratory mice
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      – SubjectFull: Opioid abuse
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      – TitleFull: Escalation of intravenous fentanyl self-administration and assessment of withdrawal behavior in male and female mice.
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              M: 06
              Text: Jun2025
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              Y: 2025
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