Exploring the addictive potential of α-methylfentanyl and acetyl-α-methylfentanyl in animal models

The abuse profiles of α-methylfentanyl and acetyl-α-methylfentanyl remain poorly characterized in preclinical models. This study systematically evaluated their addiction-related behaviours and underlying pharmacological features.

Conditioned place preference (CPP) was tested in mice with gradient doses of fentanyl, α-methylfentanyl and acetyl-α-methylfentanyl. Intravenous self-administration, behavioural economic demand curves, cue- and drug-primed reinstatement, and drug discrimination assays were conducted in rats. ED₅₀ values were calculated and compared across compounds.

All three compounds induced significant CPP, with acetyl-α-methylfentanyl showing ~ 30-fold lower potency. In self-administration, all compounds produced inverted U-shaped dose-response curves, with peak infusion rates at 0.5 µg/kg/infusion. Fentanyl exhibited the highest essential value (EV) in demand curve analysis, indicating stronger reinforcing efficacy. A single naloxone pretreatment significantly attenuated both cue- and drug-primed reinstatement. Drug discrimination ED₅₀ was 11.06, 12.65 and 128.3 µg/kg for fentanyl, α-methylfentanyl and acetyl-α-methylfentanyl, respectively.

α-methyl substitution selectively reduces reinforcing efficacy without altering reward perception; acetylation attenuates both reward and discriminative stimulus effects while preserving reinforcing capacity. µ-Opioid receptor signalling mediates relapse-like behaviour, supporting long-acting antagonists as potential interventions.