Direct comparison of the effects of functionally equivalent dosing regimens of methamphetamine, methcathinone, and α-pyrrolidinopropiophenone on behavioral and neurochemical markers of stimulant-induced neurotoxicity

Given that previous studies have provided mixed results on cathinone neurotoxicity, we compared the effects of 'functionally equivalent' dosing regimens of methamphetamine (METH), methcathinone, and α-pyrrolidinopropiophenone (α-PPP) on behavioral and neurochemical markers associated with dopaminergic alterations and cognitive function. Male Swiss Webster mice received METH (5 mg/kg), methcathinone (80 mg/kg), or α-PPP (80 mg/kg), using a 'binge'-like dosing regimen (q2h × 4, intraperitoneal). Body weight and temperature were recorded during dosing. Behavior was assessed 2-4 days later, followed by brain extraction. Motor function was evaluated by open-field testing and stride length analysis. Cognitive function was assessed with the passive avoidance test. Striatal levels of dopamine and its major metabolites were measured using ultra-HPLC. All three drug treatments induced weight loss. METH treatment produced a small, transient increase in rectal temperature (~1 °C); methcathinone and α-PPP did not. All three drug treatments impaired passive avoidance performance (P < 0.05 to P < 0.01), but none produced persistent motor deficits. METH and methcathinone treatment significantly reduced striatal dopamine levels (P < 0.001), whereas α-PPP did not, and only METH treatment increased homovanillic acid/dopamine turnover (P < 0.01). Only METH exposure triggered measurable changes in dopamine metabolism and a small, transient increase in temperature, highlighting its distinct neurochemical profile compared with methcathinone and α-PPP under these conditions. All three drug treatments impaired passive avoidance performance, but none caused lasting motor deficits, demonstrating that behavioral deficits can occur without persistent motor changes.