Locomotor stimulant and drug discrimination effects of five synthetic cathinones in rodents

Pharmacol Biochem Behav. 2025 Sep 18:174100. doi: 10.1016/j.pbb.2025.174100. Online ahead of print.

ABSTRACT

Synthetic cathinones are synthesized as legal alternatives to methamphetamine, cocaine and MDMA, and can produce serious health risks. The DEA identified five synthetic cathinones of interest: N-ethylpentedrone, N-ethylheptedrone, N-butylhexedrone, 4-methylpentedrone, and 4-methyl-α-ethylaminopentiophenone (4-MEAP). These compounds were tested to determine their locomotor stimulant and psychostimulant-like discriminative stimulus effects. Locomotor activity was tested in male Swiss-Webster mice to identify behaviorally active dose ranges and time courses. Discriminative stimulus effects of the five synthetic cathinones were tested in male Sprague-Dawley rats trained to discriminate cocaine (10 mg/kg, 10-min pretreatment) or methamphetamine (1 mg/kg, 10-min pretreatment) from saline vehicle. Four of the test compounds produced locomotor stimulant effects comparable in efficacy to methamphetamine and cocaine, with rank order of potency: 4-MEAP > N-ethylpentedrone > N-ethylheptedrone >4-methyl-pentedrone. N-butylhexedrone depressed locomotor activity. N-Ethylpentedrone and N-ethylheptedrone substituted for the discriminative stimulus effects produced by methamphetamine and cocaine. 4-MEAP fully substituted for methamphetamine. 4-Methylpentedrone fully substituted for cocaine, but only partially substituted for methamphetamine, while N-butylhexedrone partially substituted for cocaine in DD and failed to substitute for methamphetamine. Three of the compounds, N-ethylpentedrone, N-ethylheptedrone, and 4-MEAP produced robust psychostimulant-like effects, which suggests they will have abuse liability similar to cocaine or methamphetamine. 4-Methylpentedrone was a slow onset locomotor stimulant, and substituted for cocaine and only partially substituted for methamphetamine, which may indicate a weaker abuse liability compared to methamphetamine or cocaine. N-butylhexedrone produced weak psychostimulant-like effects, which suggests it may have limited use as a street drug on its own.

PMID:40975318 | DOI:10.1016/j.pbb.2025.174100