Rationale <p>People with autism spectrum disorder (ASD) often have psychiatric comorbidities, with attention deficit hyperactivity disorder (ADHD) being the most common. Psychostimulants used as ADHD treatments are less effective in these dual diagnosis individuals, with lower rates of symptom improvement and a higher incidence of adverse drug effects. The mutant BTBR T⁺ Itpr3^tf/J mouse (BTBR) may serve as a model for comorbid ADHD and ASD, however, few studies have assessed the effects of psychostimulants in these animals.</p> Objectives <p>We determined dose-effect curves for locomotor effects of 10 different psychostimulants in adult male BTBR and C57Bl/6&#xa0;N (C57) mice, including amphetamine and other monoamine releasers, methylphenidate and other reuptake inhibitors, as well as some drugs with a mixed profile of monoamine release and reuptake inhibition.</p> Methods <p>Mice were surgically implanted with radiotelemetry probes which measured locomotor activity within the home cage.</p> Results <p>A robust strain difference was typically observed at large doses, wherein C57 mice entered motor stereotypy while BTBRs did not. This resistance to stereotypy in BTBR mice resulted in dramatically increased locomotor stimulant effects across drugs.</p> Conclusions <p>Because resistance to locomotor stereotypy in BTBRs was observed among psychostimulants with distinct mechanisms of action and selectivities for monoamine transporters, it is likely that pervasive neurobiological and/or metabolic differences in BTBR mice mediate this effect. Further studies to determine the mechanisms underlying the exaggerated locomotor responses to psychostimulants in BTBR mice are needed. Results of these studies may guide drug development efforts toward identifying more effective and better-tolerated medications for comorbid ASD with ADHD.</p>