Previous research with higher doses of stimulants focused on the dopaminergic effects of these compounds in subcortical structures. Methylphenidate and amphetamine were known to block the dopamine transporter and enhance dopamine release, and robust increases in dopamine release were observed in the nucleus accumbens (Segal and Kuczenski, 1999) and dorsal striatum (Kuczenski and Segal, 1997) of rats given high doses of stimulants. Supportive evidence was found in human imaging studies, where intravenous stimulant administration displaced D2 receptor PET ligands, an indication of increased endogenous dopamine release (Volkow et al, 2002b). This measure of D2 receptor stimulation correlated with measures of reinforcement, consistent with the rodent work (Volkow et al, 2002b). In contrast, oral administration of lower doses of stimulants produces more subtle and slower effects on striatal dopamine release (Volkow et al, 2002a). The amount of dopamine release in the nucleus accumbens is especially pertinent to drug abuse, and thus rodent studies focused on this brain region to try to determine whether the doses of stimulants given to children would alter dopamine release in this structure. Kuczenski and Segal (2002, 2005) first identified the dose regimen of orally administered, low doses that produced blood levels similar to those observed in children taking stimulants to treat ADHD symptoms. They found that these low, oral doses had little or no effect on DA release in the nucleus accumbens, and they found no evidence of stimulant sensitization following low-dose chronic usage. These results in rats are consistent with observations of children taking stimulants: ADHD medications do not produce euphoria (indeed, dysphoria is the more likely side effect), and the incidence of drug abuse is actually reduced in properly medicated ADHD patients (Hechtman and Greenfield, 2003; Katusic et al, 2005).

Although Kuczenski and Segal (2002) found only subtle effects of low-dose oral methylphenidate on dopamine release in the nucleus accumbens, they did observe increased release of norepinephrine in the hippocampus. Based on this seminal paper, Berridge et al (2006) then explored low-dose stimulant effects on dopamine and norepinephrine release in the prefrontal cortex, a brain region closely linked to ADHD, as well as in the nucleus accumbens and medial septal area. A summary of these results can be seen in Figure 1. As with Kuczenski and Segal, only subtle effects were observed in accumbens dopamine release. There was also some subcortical norepinephrine release in the medial septal area. However, the greatest effects were observed in prefrontal cortex, where there were especially high levels of norepinephrine release (400% increase; Figure 1a), and significant levels of dopamine release (250% increase; Figure 1b). The functional ramifications of enhanced catecholamine release in prefrontal cortex are discussed below. It is noteworthy that atomoxetine (Strattera) also increases norepinephrine and dopamine release in the prefrontal cortex (Bymaster et al, 2002); thus, catecholamine release in the prefrontal cortex may be a common action for many ADHD therapeutics. It should be noted that available PET and SPECT neuroreceptor ligands are generally unable to detect the delicate catecholamine input to cortex. Thus, current imaging methods are limited to the striatum. Research is in progress to visualize catecholamine actions in the prefrontal cortex of human subjects.