Elsevier

Biological Psychiatry

Volume 60, Issue 10, 15 November 2006, Pages 1111-1120
Biological Psychiatry

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

https://doi.org/10.1016/j.biopsych.2006.04.022Get rights and content

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.

Section snippets

Animals and Surgery

Male Sprague-Dawley rats (290–370 g; Charles River, Wilmington, Massachusetts) had ad libitum access to food and water. For microdialysis testing, a microdialysis probe was lowered into the PFC (A+3.2; L1.0; V-5.0 at an angle of 4° lateral), the core subregion of the ACC (A+1.7; L1.4; V-7.8), or the MSA (A-.7; L.5; V-7.8) on the day before testing, as described previously (Berridge and Stalnaker 2002). Electroencephalographic and electromyographic electrodes were implanted, as described below.

Plasma Levels of MPH after Oral and IP Administration

Clinically, psychostimulants are administered orally and exert therapeutic actions at low doses when plasma concentrations are within the range of 8–40 ng/mL (Swanson and Volkow 2001). Previous studies estimated that similar plasma levels are obtained in rats after oral administration of 1.0–3.0 mg/kg (Kuczenski and Segal 2002). We obtained similar results with orally administered MPH at a dose of 2.0 mg/kg (n = 7), which resulted in plasma levels of 22 ± 7 ng/mL 15 min after drug

Overview of Results

Despite the widespread use of low-dose psychostimulants in the treatment of ADHD, surprisingly little is known about the neural mechanisms that underlie the therapeutic actions of these drugs. The current studies provide the novel observation that, when administered at low-doses that enhance cognitive function, MPH preferentially activates DA and NE efflux within the PFC relative to subcortical regions. Moreover, the effect of low-dose MPH on NE efflux within the MSA was comparable to that

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