Locomotor and discriminative stimulus effects of fluorinated analogs of amphetamine and methamphetamine in mice and rats

The prevalence of fluorinated amphetamine and methamphetamine analogs on the illicit market has continued to increase in the past decade. The perceived ability of these compounds to bypass legal regulation has resulted in an increasing popularity among drug users; however, their use produces significant adverse effects, including heart failure, cerebral hemorrhage, and death. This study aimed to investigate the effects of phenyl ring fluorination on the abuse potential of 5 synthetic stimulant compounds: 2- and 3-fluoroamphetamine (FA) and 2-, 3-, and 4-fluoromethamphetamine (FMA). The open-field assay was used to observe the locomotor effects of the compounds and to evaluate effective dose ranges and time courses for psychoactive effects in male Swiss-Webster mice. Discriminative stimulus effects were evaluated using male Sprague-Dawley rats trained to discriminate methamphetamine from saline using an fixed-ratio 10 food-maintained reinforcement schedule in a 2-lever operant box. The compounds tested all resulted in time- and dose-dependent stimulation of locomotor activity. Potencies (ED₅₀) ranged from 0.38 to 7.38 mg/kg, with rank-order potency of 2-FMA > methamphetamine > 3-FMA = 3-FA = 2-FMA > 4-FMA. Peak effects varied, with 2-FA, 3-FA, and 3-FMA showing peak effects similar to methamphetamine (5905-7758 counts), while 2-FMA and 4-FMA were weak stimulants with lower peak effects (2200-3980 counts). All fluorinated compounds elicited dose-dependent full substitution for methamphetamine with comparable potencies (ED₅₀ values = 0.32-0.71 mg/kg). The present study indicates that these analogs may have a potential for abuse comparable to that of methamphetamine, although self-administration studies need to be conducted to confirm this, and the locomotor activity data highlight possible mechanistic differences between the positional analogs through the contrasting potencies and efficacies. SIGNIFICANCE STATEMENT: Fluorinated amphetamine analogs have appeared on the illicit market and produce significant adverse effects. The present study shows that these analogs produce methamphetamine-like locomotor stimulant and discriminative stimulus effects and so may have a potential for abuse comparable to that of methamphetamine and other psychostimulants.