Determining methamphetamine doses that produce comparable and stable locomotor activity in male and female rats using dose escalation and repeated administration

Biological sex influences sensitivity to the stimulant and toxic effects of methamphetamine (METH) in both humans and rodents, with females exhibiting greater behavioral responsiveness than males. The clinical treatment target of METH-induced agitation is defined by behavioral presentation rather than a known degree of drug exposure. Therefore, the preclinical locomotor activity model of agitation would benefit from dosing strategies that produce comparable behavioral effects across sexes. This study aimed to identify sex-equivalent METH doses in rats with escalating injections of METH (0.1-1.0 mg/kg; subcutaneous), producing predominantly locomotor activity rather than stereotyped movements. It also evaluated the stability of the minimally effective doses' effects within each sex. In males and females, respectively, 0.32 and 0.1 mg/kg METH produced a comparable, significant (P < 0.05) increase in activity compared with saline. A maximal locomotor effect resulted from 0.75 mg/kg METH in male rats, which was comparable to 0.32 mg/kg in females. While the locomotor effect plateaued with 0.75 mg/kg METH in male rats, activity continued to increase with the 1 mg/kg dose in female rats. Subsequent repetition of the lower, sex-equivalent METH doses produced overall similar activity between and within sexes over 3 days. These results will inform METH dosing in future preclinical sex-comparison studies of novel interventions for the treatment of METH-induced agitation. By aligning preclinical dosing with behavioral effects rather than absolute exposure, this framework enhances the translational relevance of preclinical agitation models and improves their applicability to the evaluation of sex-inclusive pharmacotherapies for acute METH toxicity in clinical settings.