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Lisdexamfetamine dimesylate is a novel prodrug approved in North America, Europe and Brazil for treating attention deficit hyperactivity disorder (ADHD). It undergoes rate-limited hydrolysis by red blood cells to yield d-amphetamine. Following our previous work comparing lisdexamfetamine with d-amphetamine, the neurochemical and behavioural profiles of lisdexamfetamine, methylphenidate and modafinil were compared by dual-probe microdialysis in the prefrontal cortex (PFC) and striatum of conscious rats with simultaneous locomotor activity measurement. We employed pharmacologically equivalent doses of all compounds and those that spanned the therapeutically relevant and psychostimulant range. Lisdexamfetamine (0.5, 1.5, 4.5 mg/kg d-amphetamine base, per os (po)), methylphenidate (3, 10, 30 mg/kg base, po) and modafinil (100, 300, 600 mg/kg base, po) increased efflux of dopamine and noradrenaline in PFC, and dopamine in striatum. Only lisdexamfetamine increased 5-hydroxytryptamine (5-HT) efflux in PFC and striatum. Lisdexamfetamine had larger and more sustained effects on catecholaminergic neurotransmission than methylphenidate or modafinil. Linear correlations were observed between striatal dopamine efflux and locomotor activity for lisdexamfetamine and methylphenidate, but not modafinil. Regression slopes revealed greater increases in extracellular dopamine could be elicited without producing locomotor activation by lisdexamfetamine than methylphenidate. These results are consistent with clinical findings showing that lisdexamfetamine is an effective ADHD medication with prolonged duration of action and good separation between its therapeutic actions and stimulant side-effects.

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