Xylazine does not enhance fentanyl reinforcement in rats: A behavioral economic analysis

The adulteration of illicit fentanyl with the alpha-2 agonist xylazine has been designated an emerging public health threat. The clinical rationale for combining fentanyl with xylazine is currently unclear, and the inability to study fentanyl/xylazine interactions in humans warrants the need for pre...

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Bibliographic Details
Published in:Drug and alcohol dependence 2024-05, Vol.258, p.111282-111282, Article 111282
Main Authors: St. Onge, Celsey M., Canfield, Jeremy R., Ortiz, Allison, Sprague, Jon E., Banks, Matthew L.
Format: Article
Language:English
Subjects:
Behavioral economics
Drug self-administration
Fentanyl
Rat
Xylazine
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Summary:The adulteration of illicit fentanyl with the alpha-2 agonist xylazine has been designated an emerging public health threat. The clinical rationale for combining fentanyl with xylazine is currently unclear, and the inability to study fentanyl/xylazine interactions in humans warrants the need for preclinical research. We studied fentanyl and xylazine pharmacodynamic and pharmacokinetic interactions in male and female rats using drug self-administration behavioral economic methods. Fentanyl, but not xylazine, functioned as a reinforcer under both fixed-ratio and progressive-ratio drug self-administration procedures. Xylazine combined with fentanyl at three fixed dose-proportion mixtures did not significantly alter fentanyl reinforcement as measured using behavioral economic analyses. Xylazine produced a proportion-dependent decrease in the behavioral economic Q0 endpoint compared to fentanyl alone. However, xylazine did not significantly alter fentanyl self-administration at FR1. Fentanyl and xylazine co-administration did not result in changes to pharmacokinetic endpoints. The present results demonstrate that xylazine does not enhance the addictive effects of fentanyl or alter fentanyl plasma concentrations. The premise for why illicitly manufacture fentanyl has been adulterated with xylazine remains to be determined. [Display omitted] •Fentanyl, but not xylazine, functioned as a reinforcer.•Increasing proportions of xylazine did not alter fentanyl essential value.•Increasing proportions of xylazine decreased Q0.•Xylazine did not alter fentanyl pharmacokinetic measures.
ISSN:0376-8716
1879-0046
DOI:10.1016/j.drugalcdep.2024.111282