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.
Berridge
Craig W
CW
Psychology Department, University of Wisconsin, Madison, WI 53706, USA. Berridge@wisc.edu
Devilbiss
David M
DM
Andrzejewski
Matthew E
ME
Arnsten
Amy F T
AF
Kelley
Ann E
AE
Schmeichel
Brooke
B
Hamilton
Christina
C
Spencer
Robert C
RC
D018759:Adrenergic Uptake Inhibitors / Q000097:blood / Q000494:pharmacology*; D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal; D001923:Brain Chemistry / Q000187:drug effects*; D002395:Catecholamines / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D003071:Cognition / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004333:Drug Administration Routes; D004569:Electroencephalography / Q000379:methods; D004576:Electromyography / Q000379:methods; D008297:Male; D008570:Memory, Short-Term / Q000187:drug effects; D008774:Methylphenidate / Q000097:blood / Q000494:pharmacology*; D017551:Microdialysis / Q000379:methods; D009043:Motor Activity / Q000187:drug effects; D017397:Prefrontal Cortex / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017603:Signal Detection, Psychological / Q000187:drug effects; D012890:Sleep / Q000187:drug effects; D014785:Vision, Ocular / Q000187:drug effects
D018759:Adrenergic Uptake Inhibitors; D002395:Catecholamines; D008774:Methylphenidate