European journal of pharmacology · 2026
Reinforcing and discriminative stimulus effects of 4-fluorobutyrfentanyl, 4-fluoroisobutyrfentanyl, and isobutyrfentanyl in male rats.
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Lai Miaojun, Wen Lili, Li Haixia, Fu Dan, Xu Zemin, Jin Qun, Shi Baobao, Zhou Wenhua, Liu Li, Xu Peng
Аннотация
RATIONALE: 4-fluorobutyrfentanyl (4F-BF), 4-fluoroisobutyrfentanyl (4F-iBF), and isobutyrfentanyl (iBF) are isomers of butyrfentanyl. Despite these fentanyl analogs being directly involved in numerous fatal overdoses, their abuse liability profiles have yet to be fully elucidated.
OBJECTIVES: This study evaluated the reinforcing effects of 4F-BF, 4F-iBF, and iBF on drug self-administration and their relationship to the interoceptive effects of heroin via drug discrimination.
METHODS: Rats were trained to self-administer heroin (50 μg/kg/inf) under a fixed ratio (FR) 1 schedule. After 10 days of acquisition, dose response curves were generated for heroin, fentanyl, 4F-BF, 4F-iBF, and iBF. Separate cohorts of rats were trained to self-administer heroin (50 μg/kg/inf), fentanyl (2.5 μg/kg/inf), 4F-BF (25 μg/kg/inf), 4F-iBF (25 μg/kg/inf), or iBF (25 μg/kg/inf) under the FR1 schedule, followed by behavioral economic analysis to assess their reinforcing efficacy. In drug discrimination tests, rats trained to discriminate heroin (400 μg/kg) from saline underwent substitution tests for fentanyl, and fentanyl analogs.
RESULTS: 4F-BF, 4F-iBF, and iBF showed inverted U-shaped dose-response curves; the reinforcing potency of three analogs was comparable and intermediate between that of fentanyl and heroin. Rats acquired self-administration of three analogs, and behavioral economic analysis ranked their reinforcing efficacy as follows: iBF > 4F-iBF ≈ 4F-BF > fentanyl ≈ heroin. Each compound elicited full discriminative stimulus effects of heroin, with a potency order of fentanyl > 4F-iBF ≈ 4F-BF ≈ iBF > heroin.
CONCLUSIONS: These findings highlight the significant abuse liability of 4F-iBF, 4F-BF, and iBF, suggesting that these compounds pose a unique threat to public health.
OBJECTIVES: This study evaluated the reinforcing effects of 4F-BF, 4F-iBF, and iBF on drug self-administration and their relationship to the interoceptive effects of heroin via drug discrimination.
METHODS: Rats were trained to self-administer heroin (50 μg/kg/inf) under a fixed ratio (FR) 1 schedule. After 10 days of acquisition, dose response curves were generated for heroin, fentanyl, 4F-BF, 4F-iBF, and iBF. Separate cohorts of rats were trained to self-administer heroin (50 μg/kg/inf), fentanyl (2.5 μg/kg/inf), 4F-BF (25 μg/kg/inf), 4F-iBF (25 μg/kg/inf), or iBF (25 μg/kg/inf) under the FR1 schedule, followed by behavioral economic analysis to assess their reinforcing efficacy. In drug discrimination tests, rats trained to discriminate heroin (400 μg/kg) from saline underwent substitution tests for fentanyl, and fentanyl analogs.
RESULTS: 4F-BF, 4F-iBF, and iBF showed inverted U-shaped dose-response curves; the reinforcing potency of three analogs was comparable and intermediate between that of fentanyl and heroin. Rats acquired self-administration of three analogs, and behavioral economic analysis ranked their reinforcing efficacy as follows: iBF > 4F-iBF ≈ 4F-BF > fentanyl ≈ heroin. Each compound elicited full discriminative stimulus effects of heroin, with a potency order of fentanyl > 4F-iBF ≈ 4F-BF ≈ iBF > heroin.
CONCLUSIONS: These findings highlight the significant abuse liability of 4F-iBF, 4F-BF, and iBF, suggesting that these compounds pose a unique threat to public health.