¹Department of Neurobiology, Yale University School of Medicine, New Haven, CT, USA

Correspondence: Dr AFT Arnsten, Department of Neurobiology, Yale University School of Medicine, 333 Cedar Street, SHM B428, PO Box 208001, New Haven, CT 06510-8001, USA. Tel: +1 203 785 4431; Fax: +1 203 785 5263; E-mail: amy.arnsten@yale.edu

Received 17 January 2006; Revised 15 March 2006; Accepted 21 March 2006; Published online 19 July 2006.

Abstract

Stimulants such as methylphenidate and amphetamine are currently the most common treatment for attention deficit hyperactivity disorder (ADHD). For years, it was assumed that stimulants had paradoxical calming effects in ADHD patients, whereas stimulating 'normal' individuals and producing locomotor activation in rats. It is now known that low doses of stimulants focus attention and improve executive function in both normal and ADHD subjects. Furthermore, the seminal work of Kuczenski and Segal showed that low, oral doses of methylphenidate reduce locomotor activity in rats as well. Berridge et al have now shown that these low doses produce marked increases in norepinephrine and dopamine release in the prefrontal cortex, whereas having only subtle effects on subcortical catecholamine release. ihe prefrontal cortex regulates behavior and attention using representational knowledge, and imaging and neuropsychological studies have shown that the prefrontal cortex is weaker in subjects with ADHD. This cortical area is very sensitive to levels of catecholamines: moderate levels engage postsynaptic 2A-adrenoceptors and D1 receptors and improve prefrontal regulation of behavior and attention, while high levels impair prefrontal function via 1-adrenoceptors and excessive D1 receptor stimulation. Administering low doses of methylphenidate to rats improves the working memory and attentional functions of the prefrontal cortex, while high doses impair working memory and produce a perseverative pattern of errors similar to that seen in patients. The low dose improvement is hiocked by either an 2-adrenoceptor or Dl receptor antagonist, suggesting that both norepinephrine and dopamine contribute to the beneficial actions of stimulant medications.