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.