Reinforcing and discriminative stimulus effects of 4-fluorobutyrfentanyl, 4-fluoroisobutyrfentanyl, and isobutyrfentanyl in male rats.

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.