Methylphenidate Preferentially Increases Catecholamine Neurotransmission within the Prefrontal Cortex at Low Doses that Enhance Cognitive Function

Background: Low doses of psychostimulants, such as methylphenidate (MPH), are widely used in the treatment of attention-deficit/hyperactivity disorder (ADHD). Surprisingly little is known about the neural mechanisms that underlie the behavioral/cognitive actions of these drugs. The prefrontal cortex (PFC) is implicated in ADHD. Moreover, dopamine (DA) and norepinephrine (NE) are important modulators of PFC-dependent cognition. To date, the actions of low-dose psychostimulants on PFC DA and NE neurotransmission are unknown. Methods: In vivo microdialysis was used to compare the effects of low-dose MPH on NE and DA efflux within the PFC and select subcortical fields in male rats. Doses used (oral, 2.0 mg/kg; intraperitoneal, .25-1.0 mg/kg) were first determined to produce clinically relevant plasma concentrations and to facilitate both PFC-dependent attention and working memory. Results: At low doses that improve PFC-dependent cognitive function and that are devoid of locomotor-activating effects, MPH substantially increases NE and DA efflux within the PFC. In contrast, outside the PFC these doses of MPH have minimal impact on NE and DA efflux. Conclusions: The current observations suggest that the therapeutic actions of low-dose psychostimulants involve the preferential activation of catecholamine neurotransmission within the PFC.